The protein modifier UFM1 is primarily conjugated to lysine residues of the large ribosomal subunit protein RPL26. Loss of UFMylation affects diverse cellular processes, raising the question of whether additional proteins are UFMylated. We discuss challenges in identifying bona fide UFMylation clients and propose criteria for their validation.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
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
References
Walczak, C. P. et al. Ribosomal protein RPL26 is the principal target of UFMylation. Proc. Nat. Acad. Sci. USA 116, 1299–1308 (2019).
Wang, L. et al. UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis. Cell Res. 30, 5–20 (2020).
DaRosa, P. A. et al. UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER. Nature 627, 445–452 (2024).
Makhlouf, L. et al. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature 627, 437–444 (2024).
Cappadocia, L. & Lima, C. D. Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chem. Rev. 118, 889–918 (2018).
Komatsu, M., Noda, N. N. & Inada, T. The mechanistic basis and cellular functions of UFMylation. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-025-00944-y (2026).
Peter, J. J. et al. A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation. EMBO J. 41, e111015 (2022).
Millrine, D. et al. Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation. Cell Rep. 40, 111168 (2022).
Kumar, M. et al. UFC1 reveals the multifactorial and plastic nature of oxyanion holes in E2 conjugating enzymes. Nat. Commun. 16, 3912 (2025).
Wu, J., Lei, G., Mei, M., Tang, Y. & Li, H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. J. Biol. Chem. 285, 15126–15136 (2010).
Blazev, R. et al. Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS. Cell Rep. Methods 5, 101048 (2025).
Yang, S. et al. UFMylation safeguards human hepatocyte differentiation and liver homeostasis by regulating ribosome dissociation. Cell Rep. 44, 115686 (2025).
Picchianti, L. et al. Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy. EMBO J. 42, e112053 (2023).
Adamson, B. et al. A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response. Cell 167, 1867–1882.e21 (2016).
González-Quiroz, M. et al. When endoplasmic reticulum proteostasis meets the DNA damage response. Trends Cell Biol. 30, 881–891 (2020).
Acknowledgements
The work in R.R.K.’s lab is funded by National Institutes of Health grant 1R01GM148477. We thank C. Riepe and other members of the Kopito lab for discussions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks Yogesh Kulathu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Supplementary information
Rights and permissions
About this article
Cite this article
Scavone, F., Kopito, R.R. Evaluating evidence for UFMylation client diversity. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-026-00951-7
Published:
Version of record:
DOI: https://doi.org/10.1038/s41580-026-00951-7
