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The expanding repertoire of ESCRT functions in cell biology and disease

Nature volume 642, pages 877–888 (2025)Cite this article

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Abstract

The endosomal sorting complex required for transport (ESCRT) is a multicomplex machinery comprising proteins that are conserved from bacteria to humans and has diverse roles in regulating the dynamics of cellular membranes. ESCRT functions have far-reaching consequences for cell biological processes such as intracellular traffic, membrane repair, cell signalling, metabolic regulation, cell division and genome maintenance. Here we review recent insights that emphasize the pathophysiological consequences of ESCRT dysfunctions, including infections, immune disorders, cancers and neurological diseases. We highlight the possibilities of using our knowledge about ESCRT structures and functions for drug discovery.

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Fig. 1: ESCRTs in reverse-topology membrane scission.
Fig. 2: Cellular functions of ESCRTs.
Fig. 3: ESCRTs in immunity and cancer.
Fig. 4: Overview of pathologic events linked to ESCRT proteins or ESCRT pathway function in neurodegenerative diseases.

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References

  1. Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106, 145–155 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Babst, M., Katzmann, D. J., Snyder, W. B., Wendland, B. & Emr, S. D. Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev. Cell 3, 283–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Babst, M., Katzmann, D. J., Estepa-Sabal, E. J., Meerloo, T. & Emr, S. D. Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev. Cell 3, 271–282 (2002). References 1–3 identify ESCRT-I–III through genetic and biochemical analyses of Saccharomyces cerevisiae vacuolar protein sorting mutants.

    Article  CAS  PubMed  Google Scholar 

  4. Hurley, J. H. & Hanson, P. I. Membrane budding and scission by the ESCRT machinery: it’s all in the neck. Nat. Rev. Mol. Cell Biol. 11, 556–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Henne, W. M., Stenmark, H. & Emr, S. D. Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb. Perspect. Biol. 5, a016766 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schoneberg, J., Lee, I. H., Iwasa, J. H. & Hurley, J. H. Reverse-topology membrane scission by the ESCRT proteins. Nat. Rev. Mol. Cell Biol. 18, 5–17 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. McCullough, J., Frost, A. & Sundquist, W. I. Structures, functions, and dynamics of ESCRT-III/Vps4 membrane remodeling and fission complexes. Annu. Rev. Cell Dev. Biol. 34, 85–109 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Allison, R. et al. An ESCRT–spastin interaction promotes fission of recycling tubules from the endosome. J. Cell Biol. 202, 527–543 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mast, F. D. et al. ESCRT-III is required for scissioning new peroxisomes from the endoplasmic reticulum. J. Cell Biol. 217, 2087–2102 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCullough, J. et al. Structure and membrane remodeling activity of ESCRT-III helical polymers. Science 350, 1548–1551 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Stuffers, S., Sem Wegner, C., Stenmark, H. & Brech, A. Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10, 925–937 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Strack, B., Calistri, A., Craig, S., Popova, E. & Gottlinger, H. G. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 114, 689–699 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. von Schwedler, U. K. et al. The protein network of HIV budding. Cell 114, 701–713 (2003).

    Article  Google Scholar 

  15. Christ, L. et al. ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission. J. Cell Biol. 212, 499–513 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Flower, T. G. et al. A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission. Nat. Struct. Mol. Biol. 27, 570–580 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hanson, P. I., Roth, R., Lin, Y. & Heuser, J. E. Plasma membrane deformation by circular arrays of ESCRT-III protein filaments. J. Cell Biol. 180, 389–402 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lata, S. et al. Helical structures of ESCRT-III are disassembled by VPS4. Science 321, 1354–1357 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shim, S., Kimpler, L. A. & Hanson, P. I. Structure/function analysis of four core ESCRT-III proteins reveals common regulatory role for extreme C-terminal domain. Traffic 8, 1068–1079 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Schoneberg, J. et al. ATP-dependent force generation and membrane scission by ESCRT-III and Vps4. Science 362, 1423–1428 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Azad, K. et al. Structural basis of CHMP2A–CHMP3 ESCRT-III polymer assembly and membrane cleavage. Nat. Struct. Mol. Biol. 30, 81–90 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, B., Stjepanovic, G., Shen, Q., Martin, A. & Hurley, J. H. Vps4 disassembles an ESCRT-III filament by global unfolding and processive translocation. Nat. Struct. Mol. Biol. 22, 492–498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Han, H., Monroe, N., Sundquist, W. I., Shen, P. S. & Hill, C. P. The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. eLife 6, e31324 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Raiborg, C. et al. FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes. J. Cell Sci. 114, 2255–2263 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Wenzel, E. M. et al. Concerted ESCRT and clathrin recruitment waves define the timing and morphology of intraluminal vesicle formation. Nat. Commun. 9, 2932 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bache, K. G., Raiborg, C., Mehlum, A. & Stenmark, H. STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes. J. Biol. Chem. 278, 12513–12521 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Ren, X. & Hurley, J. H. VHS domains of ESCRT-0 cooperate in high-avidity binding to polyubiquitinated cargo. EMBO J. 29, 1045–1054 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raiborg, C. et al. Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nat. Cell Biol. 4, 394–398 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Katzmann, D. J., Stefan, C. J., Babst, M. & Emr, S. D. Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J. Cell Biol. 162, 413–423 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bache, K. G., Brech, A., Mehlum, A. & Stenmark, H. Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J. Cell Biol. 162, 435–442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu, X. M. et al. ESCRTs cooperate with a selective autophagy receptor to mediate vacuolar targeting of soluble cargos. Mol. Cell 59, 1035–1042 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Kostelansky, M. S. et al. Molecular architecture and functional model of the complete yeast ESCRT-I heterotetramer. Cell 129, 485–498 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wunderley, L., Brownhill, K., Stefani, F., Tabernero, L. & Woodman, P. The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex. J. Cell Sci. 127, 663–672 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Boura, E. et al. Solution structure of the ESCRT-I and -II supercomplex: implications for membrane budding and scission. Structure 20, 874–886 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wollert, T. & Hurley, J. H. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 464, 864–869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liese, S. et al. Protein crowding mediates membrane remodeling in upstream ESCRT-induced formation of intraluminal vesicles. Proc. Natl Acad. Sci. USA 117, 28614–28624 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Teis, D., Saksena, S., Judson, B. L. & Emr, S. D. ESCRT-II coordinates the assembly of ESCRT-III filaments for cargo sorting and multivesicular body vesicle formation. EMBO J. 29, 871–883 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Babst, M., Sato, T. K., Banta, L. M. & Emr, S. D. Endosomal transport function in yeast requires a novel AAA-type ATPase, Vps4p. EMBO J. 16, 1820–1831 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stuchell-Brereton, M. D. et al. ESCRT-III recognition by VPS4 ATPases. Nature 449, 740–744 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Adell, M. A. Y. et al. Recruitment dynamics of ESCRT-III and Vps4 to endosomes and implications for reverse membrane budding. eLife 6, e31652 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).

    Article  PubMed  Google Scholar 

  42. Wang, L., Klionsky, D. J. & Shen, H. M. The emerging mechanisms and functions of microautophagy. Nat. Rev. Mol. Cell Biol. 24, 186–203 (2023).

    Article  CAS  PubMed  Google Scholar 

  43. Li, J. & Hochstrasser, M. Selective microautophagy of proteasomes is initiated by ESCRT-0 and is promoted by proteasome ubiquitylation. J. Cell Sci. 135, jcs259393 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang, X. et al. TORC1 regulates vacuole membrane composition through ubiquitin- and ESCRT-dependent microautophagy. J. Cell Biol. 219, e201902127 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Mejlvang, J. et al. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J. Cell Biol. 217, 3640–3655 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Loi, M., Raimondi, A., Morone, D. & Molinari, M. ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress. Nat. Commun. 10, 5058 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Liao, Y. C. et al. COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites. Dev. Cell 59, 1410–1424.e1414 (2024).

    Article  CAS  PubMed  Google Scholar 

  48. Prashar, A. et al. Lysosomes drive the piecemeal removal of mitochondrial inner membrane. Nature 632, 1110–1117 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Morita, E. et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 26, 4215–4227 (2007). References 49,50 demonstrate the importance of ESCRTs for cytokinetic abscission and show that ALIX and TSG101 are recruited to the midbody by binding to CEP55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lie-Jensen, A. et al. Centralspindlin recruits ALIX to the midbody during cytokinetic abscission in Drosophila via a mechanism analogous to virus budding. Curr. Biol. 29, 3538–3548.e7 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Guizetti, J. et al. Cortical constriction during abscission involves helices of ESCRT-III-dependent filaments. Science 331, 1616–1620 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Elia, N., Sougrat, R., Spurlin, T. A., Hurley, J. H. & Lippincott-Schwartz, J. Dynamics of endosomal sorting complex required for transport (ESCRT) machinery during cytokinesis and its role in abscission. Proc. Natl Acad. Sci. USA 108, 4846–4851 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Goliand, I. et al. Resolving ESCRT-III spirals at the intercellular bridge of dividing cells using 3D STORM. Cell Rep. 24, 1756–1764 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Addi, C. et al. The Flemmingsome reveals an ESCRT-to-membrane coupling via ALIX/syntenin/syndecan-4 required for completion of cytokinesis. Nat. Commun. 11, 1941 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mierzwa, B. E. et al. Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodelling during cytokinesis. Nat. Cell Biol. 19, 787–798 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vietri, M. et al. Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. Nature 522, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Olmos, Y., Hodgson, L., Mantell, J., Verkade, P. & Carlton, J. G. ESCRT-III controls nuclear envelope reformation. Nature 522, 236–239 (2015). References 57,58 demonstrate that ESCRT-III mediates closure of holes in the reformed nuclear envelopes during mititoc exit, that CHMP7 recruits ESCRT-III to the reforming nuclear envelope and that the ESCRT-III protein IST1 recruits spastin to sever spindle microtubules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Olmos, Y., Perdrix-Rosell, A. & Carlton, J. G. Membrane binding by CHMP7 coordinates ESCRT-III-dependent nuclear envelope reformation. Curr. Biol. 26, 2635–2641 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. von Appen, A. et al. LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation. Nature 582, 115–118 (2020).

    Article  Google Scholar 

  61. Webster, B. M., Colombi, P., Jager, J. & Lusk, C. P. Surveillance of nuclear pore complex assembly by ESCRT-III/Vps4. Cell 159, 388–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Raab, M. et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352, 359–362 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016). References 62,63 demonstrate that ESCRT-III, recruited by CHMP7, repairs the ruptured nuclear envelope.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Coyne, A. N. et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Sci. Transl. Med. 13, eabe1923 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vietri, M. et al. Unrestrained ESCRT-III drives micronuclear catastrophe and chromosome fragmentation. Nat. Cell Biol. 22, 856–867 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Shukla, S., Larsen, K. P., Ou, C., Rose, K. & Hurley, J. H. In vitro reconstitution of calcium-dependent recruitment of the human ESCRT machinery in lysosomal membrane repair. Proc. Natl Acad. Sci. USA 119, e2205590119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jimenez, A. J. et al. ESCRT machinery is required for plasma membrane repair. Science 343, 1247136 (2014). This study demonstrates that ESCRTs are recruited to wounds in the plasma membrane to mediate their repair, and that extracellular buds are detected at the sites of ESCRT recruitment.

    Article  PubMed  Google Scholar 

  68. Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360, eaar5078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Radulovic, M. et al. ESCRT‐mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 37, e99753 (2018). References 68,69 show that Ca2+ release from damaged lysosomes triggers ESCRT recruitment, which mediates their repair and promotes cell viability.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Chen, W., Motsinger, M. M., Li, J., Bohannon, K. P. & Hanson, P. I. Ca2+-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress. Proc. Natl Acad. Sci. USA 121, e2318412121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Katoh, K. et al. The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B. Biochem. J 391, 677–685 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Missotten, M., Nichols, A., Rieger, K. & Sadoul, R. Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein. Cell Death Differ. 6, 124–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Herbst, S. et al. LRRK2 activation controls the repair of damaged endomembranes in macrophages. EMBO J. 39, e104494 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hung, Y. H., Chen, L. M., Yang, J. Y. & Yang, W. Y. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013).

    Article  PubMed  Google Scholar 

  75. Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gahlot, P. et al. Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH. Mol. Cell 84, 1556–1569 e1510 (2024).

    Article  CAS  PubMed  Google Scholar 

  77. Vargas, J. N. S., Hamasaki, M., Kawabata, T., Youle, R. J. & Yoshimori, T. The mechanisms and roles of selective autophagy in mammals. Nat. Rev. Mol. Cell Biol. 24, 167–185 (2023).

    Article  CAS  PubMed  Google Scholar 

  78. Takahashi, Y. et al. An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure. Nat. Commun. 9, 2855 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Zhen, Y. et al. ESCRT-mediated phagophore sealing during mitophagy. Autophagy 16, 826–841 (2020). References 78,79 show that ESCRT-I and ESCRT-III mediate closure of the autophagosome and that this promotes autophagic flux.

    Article  CAS  PubMed  Google Scholar 

  80. Ye, Y. et al. Identification of membrane curvature sensing motifs essential for VPS37A phagophore recruitment and autophagosome closure. Commun. Biol. 7, 334 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Javed, R. et al. Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs. EMBO J. 42, e112845 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Biol. 21, 25–42 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Votteler, J. & Sundquist, W. I. Virus budding and the ESCRT pathway. Cell Host Microbe 14, 232–241 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. VerPlank, L. et al. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55Gag. Proc. Natl Acad. Sci. USA 98, 7724–7729 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55–65 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Martin-Serrano, J., Zang, T. & Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat. Med. 7, 1313–1319 (2001). References 85–87 demonstrate that the ESCRT-I subunit TSG101, through interaction with a PTAP motif in viral Gag proteins, mediates viral budding.

    Article  CAS  PubMed  Google Scholar 

  88. Johnson, D. S., Bleck, M. & Simon, S. M. Timing of ESCRT-III protein recruitment and membrane scission during HIV-1 assembly. eLife 7, e36221 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Jackson, C. E., Scruggs, B. S., Schaffer, J. E. & Hanson, P. I. Effects of inhibiting VPS4 support a general role for ESCRTs in extracellular vesicle biogenesis. Biophys. J. 113, 1342–1352 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hoffmann, M. A. G. et al. ESCRT recruitment to SARS-CoV-2 spike induces virus-like particles that improve mRNA vaccines. Cell 186, 2380–2391.e2389 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300.e216 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yoon, S., Kovalenko, A., Bogdanov, K. & Wallach, D. MLKL, the protein that mediates necroptosis, also regulates endosomal trafficking and extracellular vesicle generation. Immunity 47, 51–65 e57 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Ruhl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018).

    Article  PubMed  Google Scholar 

  94. Liao, Y. et al. The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes. EMBO J. 42, e110780 (2023).

    Article  CAS  PubMed  Google Scholar 

  95. Claude-Taupin, A. et al. ATG9A protects the plasma membrane from programmed and incidental permeabilization. Nat. Cell Biol. 23, 846–858 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pedrera, L. et al. Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ. 28, 1644–1657 (2021).

    Article  CAS  PubMed  Google Scholar 

  97. Dai, E., Meng, L., Kang, R., Wang, X. & Tang, D. ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem. Biophys. Res. Commun. 522, 415–421 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Ritter, A. T. et al. ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack. Science 376, 377–382 (2022). This study shows that ESCRT-dependent membrane repair needs to be inhibited in cancer cells for their efficient elimination by cytotoxic T cells.

    Article  CAS  PubMed  Google Scholar 

  99. Stefani, C. et al. LITAF protects against pore-forming protein-induced cell death by promoting membrane repair. Sci. Immunol. 9, eabq6541 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li, Z. et al. Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response. Nat. Commun. 13, 6321 (2022). This proof-of-concept study demonstrates the feasibility of concomitant induction of pyroptosis and inhibition of ESCRT-mediated membrane repair for in vivo anti-tumour therapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Suda, K. et al. Plasma membrane damage limits re plicative lifespan in yeast and induces premature senescence in human fibroblasts. Nat. Aging 4, 319–335 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gros, M. et al. Endocytic membrane repair by ESCRT-III controls antigen export to the cytosol during antigen cross-presentation. Cell Rep. 40, 111205 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Maminska, A. et al. ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors. Sci. Signal. 9, ra8 (2016).

    Article  PubMed  Google Scholar 

  104. Song, D. et al. PTPN23-dependent ESCRT machinery functions as a cell death checkpoint. Nat. Commun. 15, 10364 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zanin, N. et al. STAM and Hrs interact sequentially with IFN-α receptor to control spatiotemporal JAK–STAT endosomal activation. Nat. Cell Biol. 25, 425–438 (2023).

    Article  CAS  PubMed  Google Scholar 

  106. Kvalvaag, A. et al. Clathrin mediates both internalization and vesicular release of triggered T cell receptor at the immunological synapse. Proc. Natl Acad. Sci. USA 120, e2211368120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jiang, C. et al. CRISPR/Cas9 screens reveal multiple layers of B cell CD40 regulation. Cell Rep. 28, 1307–1322.e1308 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kuchitsu, Y. et al. STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes. Nat. Cell Biol. 25, 453–466 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gentili, M. et al. ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling. Nat. Commun. 14, 611 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Balka, K. R. et al. Termination of STING responses is mediated via ESCRT-dependent degradation. EMBO J. 42, e112712 (2023). References 108–110 identify the role and mechanism of ESCRT-dependent degradation in termination of cGAS–STING signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang, Z. et al. Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy. Signal Transduct. Target. Ther. 7, 394 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu, Y. et al. Clathrin-associated AP-1 controls termination of STING signalling. Nature 610, 761–767 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Carlton, J. G., Caballe, A., Agromayor, M., Kloc, M. & Martin-Serrano, J. ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C. Science 336, 220–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sadler, J. B. A. et al. A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability. Proc. Natl Acad. Sci. USA 115, E8900–E8908 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Martin, S. et al. A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements. Science 385, eadj7446 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Di Bona, M. et al. Micronuclear collapse from oxidative damage. Science 385, eadj8691 (2024). References 115,116 explain the molecular mechanisms underlying destabilization of micronuclei, which involve reactive oxygen species and p62, as well as inhibition of ESCRT-mediated repair of micronuclear membranes.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Guan, L. et al. HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors. Nat. Commun. 13, 4078 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tomasich, E. et al. Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer. Transl. Res. 230, 21–33 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. Monypenny, J. et al. ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation. Cell Rep. 24, 630–641 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bernareggi, D. et al. CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity. Nat. Commun. 13, 1899 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Manteghi, S. et al. Haploinsufficiency of the ESCRT component HD-PTP predisposes to cancer. Cell Rep. 15, 1893–1900 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Szymanska, E. et al. Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer. EMBO Mol. Med. 12, e10812 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Neggers, J. E. et al. Synthetic lethal interaction between the ESCRT paralog enzymes VPS4A and VPS4B in cancers harboring loss of chromosome 18q or 16q. Cell Rep. 33, 108493 (2020). References 122,123 uncover the molecular basis of synthetic lethality between VPS4A and VPS4B, and its possible application in anti-cancer therapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Xu, Z., Liang, L., Wang, H., Li, T. & Zhao, M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem. Biophys. Res. Commun. 311, 1057–1066 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Wittinger, M. et al. hVps37A status affects prognosis and cetuximab sensitivity in ovarian cancer. Clin. Cancer Res. 17, 7816–7827 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Kolmus, K. et al. Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses. J. Cell Sci. 134, jcs250951 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Migliano, S. M. et al. Removal of hypersignaling endosomes by simaphagy. Autophagy 20, 769–791 (2024).

    Article  PubMed  Google Scholar 

  128. Takahashi, Y. et al. VPS37A directs ESCRT recruitment for phagophore closure. J. Cell Biol. 218, 3336–3354 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schultz, D. F. et al. Loss of HD-PTP function results in lipodystrophy, defective cellular signaling and altered lipid homeostasis. J. Cell Sci. 137, jcs262032 (2024).

    Article  CAS  PubMed  Google Scholar 

  130. Sekar, R. et al. Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes. Cell Metab. 34, 2047 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Das, D. et al. VPS4A is the selective receptor for lipophagy in mice and humans. Mol. Cell 84, 4436–4453.e8 (2024).

    Article  CAS  PubMed  Google Scholar 

  132. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Cox, L. E. et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9872 (2010). References 132,133 identify mutations in CHMP2B as genetic causes of FTD/ALS.

    Article  PubMed  PubMed Central  Google Scholar 

  134. van der Zee, J. et al. CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum. Mol. Genet. 17, 313–322 (2008).

    Article  PubMed  Google Scholar 

  135. Urwin, H. et al. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum. Mol. Genet 19, 2228–2238 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G. & Gao, F. B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Gissawong, N. et al. Electrochemical detection of methyl parathion using calix[6]arene/bismuth ferrite/multiwall carbon nanotube-modified fluorine-doped tin oxide electrode. Mikrochim. Acta 189, 461 (2022).

    Article  CAS  PubMed  Google Scholar 

  138. Holm, I. E., Englund, E., Mackenzie, I. R., Johannsen, P. & Isaacs, A. M. A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J. Neuropathol. Exp. Neurol. 66, 884–891 (2007).

    Article  PubMed  Google Scholar 

  139. Jambroes, M., Lamkaddem, M., Stronks, K. & Essink-Bot, M. L. Enumerating the preventive youth health care workforce: Size, composition and regional variation in the Netherlands. Health Policy 119, 1557–1564 (2015).

    Article  PubMed  Google Scholar 

  140. Ghazi-Noori, S. et al. Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. Brain 135, 819–832 (2012).

    Article  PubMed  Google Scholar 

  141. West, R. J. H., Ugbode, C., Fort-Aznar, L. & Sweeney, S. T. Neuroprotective activity of ursodeoxycholic acid in CHMP2B(Intron5) models of frontotemporal dementia. Neurobiol. Dis. 144, 105047 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Belly, A. et al. CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines. J. Cell Sci. 123, 2943–2954 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Heffner, C. M., Starling, G. P., Isaacs, A. M. & Carlton, J. G. The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in membrane repair. Preprint at bioRxiv https://doi.org/10.1101/2024.11.19.624330 (2024).

  144. Baskerville, V., Rapuri, S., Mehlhop, E. & Coyne, A. N. SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis. Brain 147, 109–121 (2024).

    Article  PubMed  Google Scholar 

  145. Keeley, O., Mendoza, E., Menon, D. & Coyne, A. N. CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS. Acta Neuropathol. Commun. 12, 199 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dubey, S. K., Maulding, K., Sung, H. & Lloyd, T. E. Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD. Cell Rep. 40, 111379 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Frost, B., Bardai, F. H. & Feany, M. B. Lamin dysfunction mediates neurodegeneration in tauopathies. Curr. Biol. 26, 129–136 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Eftekharzadeh, B. et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99, 925–940.e927 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Paonessa, F. et al. Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in tau-mediated frontotemporal dementia. Cell Rep. 26, 582–593.e585 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sirtori, R. et al. LINC complex alterations are a key feature of sporadic and familial ALS/FTD. Acta Neuropathol. Commun. 12, 69 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sirtori, R. et al. Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD. Preprint at bioRxiv https://doi.org/10.1101/2024.02.01.578318 (2024).

  152. Giampetruzzi, A. et al. Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis. Nat. Commun. 10, 3827 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Ortega, J. A. et al. Nucleocytoplasmic proteomic analysis uncovers eRF1 and nonsense-mediated decay as modifiers of ALS/FTD C9orf72 toxicity. Neuron 106, 90–107.e113 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Prissette, M. et al. Disruption of nuclear envelope integrity as a possible initiating event in tauopathies. Cell Rep. 40, 111249 (2022). This study examines the potential for therapeutically modulating ESCRT expression to mitigate nuclear envelope alterations in tauopathy.

    Article  CAS  PubMed  Google Scholar 

  155. Wu, J., Wu, J., Chen, T., Cai, J. & Ren, R. Protein aggregation and its affecting mechanisms in neurodegenerative diseases. Neurochem. Int. 180, 105880 (2024).

    Article  CAS  PubMed  Google Scholar 

  156. Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Uemura, N., Uemura, M. T., Luk, K. C., Lee, V. M. & Trojanowski, J. Q. Cell-to-cell transmission of tau and α-synuclein. Trends Mol. Med. 26, 936–952 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Peng, C., Trojanowski, J. Q. & Lee, V. M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Rose, K. et al. Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes. Proc. Natl Acad. Sci. USA 121, e2315690121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Chen, J. J. et al. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation. J. Biol. Chem. 294, 18952–18966 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Liu, G. et al. Endocytosis regulates TDP-43 toxicity and turnover. Nat. Commun. 8, 2092 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Borland, H. et al. α-Synuclein buildup is alleviated via ESCRT-dependent endosomal degradation brought about by p38MAPK inhibition in cells expressing p25α. J. Biol. Chem. 298, 102531 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Chou, C. C. et al. Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer’s phenotypes. Res. Sq. https://doi.org/10.21203/rs.3.rs-4407236/v1 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Nim, S. et al. Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease. Nat. Commun. 14, 2150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Spencer, B. et al. α-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum. Mol. Genet. 25, 1100–1115 (2016). References 166,167 examine modulation of ESCRT–α-synuclein interactions to alleviate neurodegeneration in Parkinson’s disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zenko, D. et al. Monitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation. Sci. Adv. 9, eadd8910 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sitron, C. S. et al. α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation. Preprint at bioRxiv https://doi.org/10.1101/2025.01.13.632710 (2025).

  169. Sowada, N. et al. Mutations of PTPN23 in developmental and epileptic encephalopathy. Hum. Genet. 136, 1455–1461 (2017).

    Article  CAS  PubMed  Google Scholar 

  170. Farazi Fard, M. A. et al. Truncating mutations in UBAP1 cause hereditary spastic paraplegia. Am. J. Hum. Genet. 104, 767–773 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Brugger, M. et al. Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy. Am. J. Hum. Genet. 111, 594–613 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rodger, C. et al. De novo VPS4A mutations cause multisystem disease with abnormal neurodevelopment. Am. J. Hum. Genet. 107, 1129–1148 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Seu, K. G. et al. VPS4A mutations in humans cause syndromic congenital dyserythropoietic anemia due to cytokinesis and trafficking defects. Am. J. Hum. Genet. 107, 1149–1156 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mochida, G. H. et al. CHMP1A encodes an essential regulator of BMI1–INK4A in cerebellar development. Nat. Genet. 44, 1260–1264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Coulter, M. E. et al. The ESCRT-III protein CHMP1A mediates secretion of sonic hedgehog on a distinctive subtype of extracellular vesicles. Cell Rep. 24, 973–986.e978 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Cohen-Barak, E. et al. A homozygous variant in CHMP3 is associated with complex hereditary spastic paraplegia. J. Med. Genet. 60, 233–240 (2023).

    Article  CAS  PubMed  Google Scholar 

  177. Vita, D. J. & Broadie, K. ESCRT-III membrane trafficking misregulation contributes to fragile X syndrome synaptic defects. Sci. Rep. 7, 8683 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Sears, J. C. & Broadie, K. Fragile X mental retardation protein regulates activity-dependent membrane trafficking and trans-synaptic signaling mediating synaptic remodeling. Front. Mol. Neurosci. 10, 440 (2017).

    Article  PubMed  Google Scholar 

  179. Sweeney, N. T., Brenman, J. E., Jan, Y. N. & Gao, F. B. The coiled-coil protein shrub controls neuronal morphogenesis in Drosophila. Curr. Biol. 16, 1006–1011 (2006).

    Article  CAS  PubMed  Google Scholar 

  180. Loncle, N., Agromayor, M., Martin-Serrano, J. & Williams, D. W. An ESCRT module is required for neuron pruning. Sci. Rep. 5, 8461 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Rheinemann, L. et al. RetroCHMP3 blocks budding of enveloped viruses without blocking cytokinesis. Cell 184, 5419–5431.e5416 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Knyazeva, A. et al. A chemical inhibitor of IST1–CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation. Proc. Natl Acad. Sci. USA 121, e2317680121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cowan, A. D. & Ciulli, A. Driving E3 ligase substrate specificity for targeted protein degradation: lessons from nature and the laboratory. Annu. Rev. Biochem. 91, 295–319 (2022).

    Article  CAS  PubMed  Google Scholar 

  184. Krone, M. W. & Crews, C. M. Next steps for targeted protein degradation. Cell Chem. Biol. 32, 219–226 (2024).

    Article  PubMed  Google Scholar 

  185. Pornillos, O., Alam, S. L., Davis, D. R. & Sundquist, W. I. Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nat. Struct. Biol. 9, 812–817 (2002).

    CAS  PubMed  Google Scholar 

  186. Demirov, D. G., Ono, A., Orenstein, J. M. & Freed, E. O. Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc. Natl Acad. Sci. USA 99, 955–960 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Ferraiuolo, R. M., Manthey, K. C., Stanton, M. J., Triplett, A. A. & Wagner, K. U. The multifaceted roles of the tumor susceptibility gene 101 (TSG101) in normal development and disease. Cancers 12, 450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank D. Fracchiolla for help with preparing figures. J.H.H. was supported by National Institutes of Health grant R37AI112442 and by Hoffmann-La Roche through the Alliance for Therapies in Neuroscience. J.H.H. and H.S. were jointly supported by the Peder Sather Grant Program. A.N.C. was supported by NIH NINDS R01NS132836, NIH NINDS/NIA R00NS123242, the Muscular Dystrophy Association and the BrightFocus Foundation. M.M. was supported by the RACE project (grant agreement 101059801) funded by the European Union under Horizon Europe and by the RACE-PRIME project carried out within the IRAP programme of the Foundation for Polish Science co-financed by the European Union under the European Funds for Smart Economy 2021–2027 (FENG). H.S. was supported by the Miller Institute for Basic Research in Science, the Norwegian Cancer Society (project 182698), the South-Eastern Norway Regional Health Authority (project 2016087), the Research Council of Norway (project 302994) and an Advanced Grant from the European Research Council (project 788954).

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    James H. Hurley & Harald Stenmark

  2. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA

    James H. Hurley

  3. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA

    James H. Hurley

  4. Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alyssa N. Coyne

  5. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alyssa N. Coyne

  6. Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland

    Marta Miączyńska

  7. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    Harald Stenmark

  8. Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway

    Harald Stenmark

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J.H.H. and H.S. coordinated writing. J.H.H., A.N.C., M.M. and H.S. wrote the initial draft, and J.H.H., A.N.C., M.M. and H.S. edited the manuscript.

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Correspondence to James H. Hurley or Harald Stenmark.

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Competing interests

A.N.C. is an inventor (50%) on US patent application number 63/111,882 filed by Johns Hopkins University on methods to modulate CHMP7 expression as a therapy for neurodegeneration. A.N.C. is an inventor (90%) on US patent application number PCT/US2025/015434 filed by Johns Hopkins University on methods to modulate CHMP2B expression as a therapy for neurodegeneration. J.H.H. is a co-founder and shareholder of Casma Therapeutics, receives research funding from Hoffman-La Roche and has consulted for Corsalex. J.H.H. is an inventor on US patent application number 63/786,223 filed by the University of California, Berkeley on selective inhibitors of VPS4B and VPS4A and their use. M.M. and H.S. declare no competing interests.

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Hurley, J.H., Coyne, A.N., Miączyńska, M. et al. The expanding repertoire of ESCRT functions in cell biology and disease. Nature 642, 877–888 (2025). https://doi.org/10.1038/s41586-025-08950-y

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