Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The mechanistic basis and cellular functions of UFMylation

Nature Reviews Molecular Cell Biology (2026)Cite this article

Subjects

Abstract

UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of the UFM1 system.
Fig. 2: Structural basis of ribosome UFMylation.
Fig. 3: UFMylation in ER-related processes.
Fig. 4: UFMylation in non-canonical processes.

Similar content being viewed by others

References

  1. Kerscher, O., Felberbaum, R. & Hochstrasser, M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22, 159–180 (2006).

    Article  PubMed  Google Scholar 

  2. Cappadocia, L. & Lima, C. D. Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chem. Rev. 118, 889–918 (2018).

    Article  PubMed  Google Scholar 

  3. Gerakis, Y., Quintero, M., Li, H. & Hetz, C. The UFMylation system in proteostasis and beyond. Trends Cell Biol. 29, 974–986 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Millrine, D., Peter, J. J. & Kulathu, Y. A guide to UFMylation, an emerging posttranslational modification. FEBS J. 290, 5040–5056 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Komatsu, M., Inada, T. & Noda, N. N. The UFM1 system: working principles, cellular functions, and pathophysiology. Mol. Cell 84, 156–169 (2024).

    Article  PubMed  Google Scholar 

  6. Komatsu, M. et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 23, 1977–1986 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tatsumi, K. et al. A novel type of E3 ligase for the Ufm1 conjugation system. J. Biol. Chem. 285, 5417–5427 (2010).

    Article  PubMed  Google Scholar 

  8. Peter, J. J. et al. A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation. EMBO J. 41, e111015 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yang, R. et al. CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development. Development 146, dev.169235 (2019).

    Article  Google Scholar 

  10. Kang, S. H. et al. Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2. J. Biol. Chem. 282, 5256–5262 (2007).

    Article  PubMed  Google Scholar 

  11. Millrine, D. et al. Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation. Cell Rep. 40, 111168 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Scavone, F., Gumbin, S. C., Da Rosa, P. A. & Kopito, R. R. RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 120, e2220340120 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Walczak, C. P. et al. Ribosomal protein RPL26 is the principal target of UFMylation. Proc. Natl Acad. Sci. USA 116, 1299–1308 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang, L. et al. SAYSD1 senses UFMylated ribosome to safeguard co-translational protein translocation at the endoplasmic reticulum. Cell Rep. 42, 112028 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang, L. et al. UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis. Cell Res. 30, 5–20 (2020).

    Article  PubMed  Google Scholar 

  16. Ishimura, R. et al. The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3. Nat. Commun. 13, 7857 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Stephani, M. et al. A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress. eLife 9, e58396 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Picchianti, L. et al. Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy. EMBO J. 42, e112053 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liang, J. R. et al. A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation. Cell 180, 1160–1177.e20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li, B. et al. Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis. Proc. Natl Acad. Sci. USA 120, e2208351120 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. DaRosa, P. A. et al. UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER. Nature 627, 445–452 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Makhlouf, L. et al. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature 627, 437–444 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ishimura, R. et al. Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control. Sci. Adv. 9, eadh3635 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gong, Y. et al. PARP1 UFMylation ensures the stability of stalled replication forks. Proc. Natl Acad. Sci. USA 121, e2322520121 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Panichnantakul, P. et al. Protein UFMylation regulates early events during ribosomal DNA-damage response. Cell Rep. 43, 114738 (2024).

    Article  PubMed  Google Scholar 

  26. Yip, M. C. J. et al. Mechanism for recycling tRNAs on stalled ribosomes. Nat. Struct. Mol. Biol. 26, 343–349 (2019).

    Article  PubMed  Google Scholar 

  27. Qin, B. et al. STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation. Sci. Adv. 6, eaax8214 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yang, S., Moy, N. & Yang, R. The UFM1 conjugation system in mammalian development. Dev. Dyn. 252, 976–985 (2023).

    Article  PubMed  Google Scholar 

  29. Wang, R. N., Li, L., Zhou, J. & Ran, J. Multifaceted roles of UFMylation in health and disease. Acta Pharmacol. Sin. https://doi.org/10.1038/s41401-024-01456-9 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Colin, E. et al. Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy. Am. J. Hum. Genet. 99, 695–703 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Muona, M. et al. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am. J. Hum. Genet. 99, 683–694 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Parra Bravo, C. et al. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187, 2446–2464.e22 (2024).

    Article  PubMed  Google Scholar 

  33. Wang, L. et al. Mono-UFMylation promotes misfolding-associated secretion of α-synuclein. Sci. Adv. 10, eadk2542 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sasakawa, H. et al. Solution structure and dynamics of Ufm1, a ubiquitin-fold modifier 1. Biochem. Biophys. Res. Commun. 343, 21–26 (2006).

    Article  PubMed  Google Scholar 

  35. Bacik, J. P., Walker, J. R., Ali, M., Schimmer, A. D. & Dhe-Paganon, S. Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme. J. Biol. Chem. 285, 20273–20280 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Oweis, W. et al. Trans-binding mechanism of ubiquitin-like protein activation revealed by a UBA5-UFM1 complex. Cell Rep. 16, 3113–3120 (2016).

    Article  PubMed  Google Scholar 

  37. Soudah, N. et al. An N-terminal extension to UBA5 adenylation domain boosts UFM1 activation: isoform-specific differences in ubiquitin-like protein activation. J. Mol. Biol. 431, 463–478 (2019).

    Article  PubMed  Google Scholar 

  38. Habisov, S. et al. Structural and functional analysis of a novel interaction motif within UFM1-activating enzyme 5 (UBA5) required for binding to ubiquitin-like proteins and ufmylation. J. Biol. Chem. 291, 9025–9041 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kumar, M. et al. Structural basis for UFM1 transfer from UBA5 to UFC1. Nat. Commun. 12, 5708 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wesch, N., Lohr, F., Rogova, N., Dotsch, V. & Rogov, V. V. A concerted action of UBA5 C-terminal unstructured regions is important for transfer of activated UFM1 to UFC1. Int. J. Mol. Sci. 22, 7390 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Taherbhoy, A. M. et al. Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway. Mol. Cell 44, 451–461 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Noda, N. N. et al. Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol. Cell 44, 462–475 (2011).

    Article  PubMed  Google Scholar 

  43. Lemaire, K. et al. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS ONE 6, e18517 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zhang, Y., Zhang, M., Wu, J., Lei, G. & Li, H. Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS ONE 7, e48587 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Banerjee, S. et al. Structural study of UFL1-UFC1 interaction uncovers the role of UFL1 N-terminal helix in ufmylation. EMBO Rep. 24, e56920 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Liang, Q. et al. Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease. J. Biol. Chem. 298, 102016 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ha, B. H. et al. Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J. Biol. Chem. 286, 10248–10257 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kim, K. H., Ha, B. H. & Kim, E. E. Structural basis for Ufm1 recognition by UfSP. FEBS Lett. 592, 263–273 (2018).

    Article  PubMed  Google Scholar 

  49. Penchev, I. et al. UFMylation orchestrates spatiotemporal coordination of RQC at the ER. Sci. Adv. 11, eadv0435 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Chen, C., Itakura, E., Weber, K. P., Hegde, R. S. & de Bono, M. An ER complex of ODR-4 and ODR-8/Ufm1 specific protease 2 promotes GPCR maturation by a Ufm1-independent mechanism. PLoS Genet. 10, e1004082 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Akinniyi, O. T. & Reese, J. C. DEF1: much more than an RNA polymerase degradation factor. DNA Repair 107, 103202 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Krumm, N. et al. Excess of rare, inherited truncating mutations in autism. Nat. Genet. 47, 582–588 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Martin, P. B. et al. NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease. Nat. Commun. 11, 4625 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Inada, T. & Beckmann, R. Mechanisms of translation-coupled quality control. J. Mol. Biol. 436, 168496 (2024).

    Article  PubMed  Google Scholar 

  55. Joazeiro, C. A. P. Mechanisms and functions of ribosome-associated protein quality control. Nat. Rev. Mol. Cell Biol. 20, 368–383 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Inada, T. Quality controls induced by aberrant translation. Nucleic Acids Res. 48, 1084–1096 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nat. Struct. Mol. Biol. 23, 7–15 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Inada, T. The ribosome as a platform for mRNA and nascent polypeptide quality control. Trends Biochem. Sci. 42, 5–15 (2017).

    Article  PubMed  Google Scholar 

  59. Sitron, C. S. & Brandman, O. Detection and degradation of stalled nascent chains via ribosome-associated quality control. Annu. Rev. Biochem. 89, 417–442 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Mochida, K. & Nakatogawa, H. ER-phagy: selective autophagy of the endoplasmic reticulum. EMBO Rep. 23, e55192 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Reggiori, F. & Molinari, M. ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum. Physiol. Rev. 102, 1393–1448 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Chino, H. & Mizushima, N. ER-phagy: quality and quantity control of the endoplasmic reticulum by autophagy. Cold Spring Harb. Perspect. Biol. 15, a041256 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Li, J. et al. Ufm1-specific ligase Ufl1 regulates endoplasmic reticulum homeostasis and protects against heart failure. Circ. Heart Fail. 11, e004917 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhou, Y. et al. Ufl1 deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis. J. Genet. Genom. 48, 403–410 (2021).

    Article  Google Scholar 

  65. Miller, C. et al. RCAD/BiP pathway is necessary for the proper synthesis of digestive enzymes and secretory function of the exocrine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G314–G326 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Wang, Z. et al. MRE11 UFMylation promotes ATM activation. Nucleic Acids Res. 47, 4124–4135 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lee, L. et al. UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival. Sci. Adv. 7, eabc7371 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tian, T. et al. UFL1 triggers replication fork degradation by MRE11 in BRCA1/2-deficient cells. Nat. Chem. Biol. 20, 1650–1661 (2024).

    Article  PubMed  Google Scholar 

  69. Qin, B. et al. UFL1 promotes histone H4 ufmylation and ATM activation. Nat. Commun. 10, 1242 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Tan, Q. & Xu, X. PTIP UFMylation promotes replication fork degradation in BRCA1-deficient cells. J. Biol. Chem. 300, 107312 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Liu, J. et al. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nat. Cell Biol. 22, 1056–1063 (2020).

    Article  PubMed  Google Scholar 

  72. Snider, D. L., Park, M., Murphy, K. A., Beachboard, D. C. & Horner, S. M. Signaling from the RNA sensor RIG-I is regulated by ufmylation. Proc. Natl Acad. Sci. USA 119, e2119531119 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yiu, S. P. T. et al. An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation. Mol. Cell 83, 2367–2386.e15 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zhou, J. et al. Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target. Proc. Natl Acad. Sci. USA 120, e2215732120 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  75. He, C. et al. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity. Mol. Cell 84, 1120–1138.e8 (2024).

    Article  PubMed  Google Scholar 

  76. Mao, M. et al. Modification of PLAC8 by UFM1 affects tumorous proliferation and immune response by impacting PD-L1 levels in triple-negative breast cancer. J. Immunother. Cancer 10, e005668 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Zhu, J. et al. P4HB UFMylation regulates mitochondrial function and oxidative stress. Free Radic. Biol. Med. 188, 277–286 (2022).

    Article  PubMed  Google Scholar 

  78. Yang, J. et al. Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J. Exp. Clin. Cancer Res. 40, 206 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Turano, C., Coppari, S., Altieri, F. & Ferraro, A. Proteins of the PDI family: unpredicted non-ER locations and functions. J. Cell Physiol. 193, 154–163 (2002).

    Article  PubMed  Google Scholar 

  80. Cai, Y. et al. UFBP1, a key component of the Ufm1 conjugation system, is essential for ufmylation-mediated regulation of erythroid development. PLoS Genet. 11, e1005643 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tatsumi, K. et al. The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nat. Commun. 2, 181 (2011).

    Article  PubMed  Google Scholar 

  82. Zhang, M. et al. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ. 22, 1922–1934 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Egunsola, A. T. et al. Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J. Clin. Invest. 127, 1475–1484 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Cai, Y. et al. Indispensable role of the ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation. Cell Discov. 5, 7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Quintero, M. et al. Cdk5rap3 is essential for intestinal Paneth cell development and maintenance. Cell Death Dis. 12, 131 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Balce, D. R. et al. UFMylation inhibits the proinflammatory capacity of interferon-γ-activated macrophages. Proc. Natl Acad. Sci. USA 118, e2011763118 (2021).

    Article  PubMed  Google Scholar 

  87. Zhou, X. et al. UFMylation: a ubiquitin-like modification. Trends Biochem. Sci. 49, 52–67 (2024).

    Article  PubMed  Google Scholar 

  88. Nahorski, M. S. et al. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 141, 1934–1945 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Zhang, J. et al. Deficiency of murine UFM1-specific E3 ligase causes microcephaly and inflammation. Mol. Neurobiol. 59, 6363–6372 (2022).

    Article  PubMed  Google Scholar 

  90. Zhang, G. et al. UFSP2-related spondyloepimetaphyseal dysplasia: a confirmatory report. Eur. J. Med. Genet. 63, 104021 (2020).

    Article  PubMed  Google Scholar 

  91. Di Rocco, M. et al. Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation. Clin. Genet. 93, 671–674 (2018).

    Article  PubMed  Google Scholar 

  92. Watson, C. M. et al. Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia. S. Afr. Med. J. 105, 558–563 (2015).

    Article  PubMed  Google Scholar 

  93. Zhou, J. et al. Genomic profiling of the UFMylation family genes identifies UFSP2 as a potential tumour suppressor in colon cancer. Clin. Transl. Med. 11, e642 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Fang, B., Li, Z., Qiu, Y., Cho, N. & Yoo, H. M. Inhibition of UBA5 expression and induction of autophagy in breast cancer cells by usenamine A. Biomolecules 11, 1348 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Chen, F. et al. Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling. J. Exp. Clin. Cancer Res. 42, 110 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Grau-Bove, X., Sebe-Pedros, A. & Ruiz-Trillo, I. The eukaryotic ancestor had a complex ubiquitin signaling system of archaeal origin. Mol. Biol. Evol. 32, 726–739 (2015).

    Article  PubMed  Google Scholar 

  98. Kwon, Y. T. & Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 42, 873–886 (2017).

    Article  PubMed  Google Scholar 

  99. Dikic, I. & Schulman, B. A. An expanded lexicon for the ubiquitin code. Nat. Rev. Mol. Cell Biol. 24, 273–287 (2023).

    Article  PubMed  Google Scholar 

  100. Vertegaal, A. C. O. Signalling mechanisms and cellular functions of SUMO. Nat. Rev. Mol. Cell Biol. 23, 715–731 (2022).

    Article  PubMed  Google Scholar 

  101. Harper, J. W. & Schulman, B. A. Cullin-RING ubiquitin ligase regulatory circuits: a quarter century beyond the F-box hypothesis. Annu. Rev. Biochem. 90, 403–429 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mizushima, N. The ATG conjugation systems in autophagy. Curr. Opin. Cell Biol. 63, 1–10 (2020).

    Article  PubMed  Google Scholar 

  103. Zhang, X. & Chen, X. L. The emerging roles of ubiquitin-like protein Urm1 in eukaryotes. Cell Signal. 81, 109946 (2021).

    Article  PubMed  Google Scholar 

  104. Hermann, M. & Bogunovic, D. ISG15: in sickness and in health. Trends Immunol. 38, 79–93 (2017).

    Article  PubMed  Google Scholar 

  105. Ye, Y. & Rape, M. Building ubiquitin chains: E2 enzymes at work. Nat. Rev. Mol. Cell Biol. 10, 755–764 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zheng, N. & Shabek, N. Ubiquitin ligases: structure, function, and regulation. Annu. Rev. Biochem. 86, 129–157 (2017).

    Article  PubMed  Google Scholar 

  107. Furukawa, K., Mizushima, N., Noda, T. & Ohsumi, Y. A protein conjugation system in yeast with homology to biosynthetic enzyme reaction of prokaryotes. J. Biol. Chem. 275, 7462–7465 (2000).

    Article  PubMed  Google Scholar 

  108. Trempe, J. F. Reading the ubiquitin postal code. Curr. Opin. Struct. Biol. 21, 792–801 (2011).

    Article  PubMed  Google Scholar 

  109. Yau, T. Y., Sander, W., Eidson, C. & Courey, A. J. SUMO interacting motifs: structure and function. Cells 10, 2825 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Noda, N. N., Ohsumi, Y. & Inagaki, F. Atg8-family interacting motif crucial for selective autophagy. FEBS Lett. 584, 1379–1385 (2010).

    Article  PubMed  Google Scholar 

  111. Birgisdottir, A. B., Lamark, T. & Johansen, T. The LIR motif — crucial for selective autophagy. J. Cell Sci. 126, 3237–3247 (2013).

    Article  PubMed  Google Scholar 

  112. Kolla, S., Ye, M., Mark, K. G. & Rape, M. Assembly and function of branched ubiquitin chains. Trends Biochem. Sci. 47, 759–771 (2022).

    Article  PubMed  Google Scholar 

  113. Vertegaal, A. C. SUMO chains: polymeric signals. Biochem. Soc. Trans. 38, 46–49 (2010).

    Article  PubMed  Google Scholar 

  114. Enchev, R. I., Schulman, B. A. & Peter, M. Protein neddylation: beyond cullin-RING ligases. Nat. Rev. Mol. Cell Biol. 16, 30–44 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Yoo, H. M. et al. Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development. Mol. Cell 56, 261–274 (2014).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI grant numbers 23K20044 and 24H00060 (to M.K.), JP25H01320 (to N.N.N.) and JP25H00007 (to T.I.). The authors thank their laboratory colleagues and Y. Dagdas for the insightful discussions. This work is dedicated to the memory of K. Tanaka, who passed away on 23 July 2024, in recognition of his profound contributions to the field.

Author information

Authors and Affiliations

  1. Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Masaaki Komatsu

  2. Autophagy Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Masaaki Komatsu

  3. Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Nobuo N. Noda

  4. Institute of Microbial Chemistry (Bikaken), Tokyo, Japan

    Nobuo N. Noda

  5. Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Toshifumi Inada

Authors
  1. Masaaki Komatsu
    View author publications

    Search author on:PubMed Google Scholar

  2. Nobuo N. Noda
    View author publications

    Search author on:PubMed Google Scholar

  3. Toshifumi Inada
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Masaaki Komatsu, Nobuo N. Noda or Toshifumi Inada.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks Yafei Cai and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Ferroptosis

A regulated, iron-dependent form of cell death driven by uncontrolled lipid peroxidation, arising from failure of the glutathione-dependent antioxidant system, and genetically and biochemically distinct from apoptosis and other programmed death pathways.

Life history strategies

Patterns of growth, reproduction and survival that characterize how an organism allocates resources across its lifespan.

Listerin

(LTN1). An E3 ubiquitin ligase in the ribosome-associated quality control (RQC) pathway that ubiquitinates nascent polypeptides on stalled ribosomes to target them for degradation.

Nuclear export mediator factor

(NEMF). A core component of the RQC machinery that recognizes stalled ribosomes and recruits downstream RQC factors.

PINK1–Parkin pathway

A mitochondrial quality control pathway in which PINK1 accumulates on damaged mitochondria and recruits or activates the E3 ligase Parkin, triggering mitophagy — the selective autophagic removal of damaged mitochondria.

RQC factors

Components of the ribosome-associated quality control pathway that detect stalled or collided ribosomes and mediate the ubiquitination, extraction or degradation of incomplete nascent chains after the dissociation of ribosomes.

SEC61 translocon

A protein-conducting channel in the endoplasmic reticulum membrane that mediates the co-translational translocation of nascent polypeptides into or across the ER membrane.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Komatsu, M., Noda, N.N. & Inada, T. The mechanistic basis and cellular functions of UFMylation. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-025-00944-y

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41580-025-00944-y

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing