Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of Molecular Cell, Mao et al. identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.

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Mao et al. demonstrate that reversible UFMylation is required to complete ER-associated ribosome quality control. The deUFMylation enzyme UFSP2 localizes to the ER via its interaction with the ER-resident protein ODR4 and functionally associates with the UFM1 E3 ligase complex to remove UFM1 from RPL26 on the 60S ribosomal subunit, thereby maintaining neuronal proteostasis.

Nature Structural & Molecular Biology, Published online: 26 May 2025; doi:10.1038/s41594-025-01576-8Zhao et al. show that Akt-mediated phosphorylation of ubiquitin-fold modifier 1 (UFM1)-specific E3 ligase 1 (UFL1) catalyzes the UFMylation of ArpC4, a core subunit of actin-related proteins 2 and 3. Through ArpC4 UFMylation, UFL1 promotes lamellipodia formation and enhances cell migration, invasion and metastasis.

Nature Structural & Molecular Biology, Published online: 26 May 2025; doi:10.1038/s41594-025-01576-8Zhao et al. show that Akt-mediated phosphorylation of ubiquitin-fold modifier 1 (UFM1)-specific E3 ligase 1 (UFL1) catalyzes the UFMylation of ArpC4, a core subunit of actin-related proteins 2 and 3. Through ArpC4 UFMylation, UFL1 promotes lamellipodia formation and enhances cell migration, invasion and metastasis.

UFMylation is the post-translational modification of Ubiquitin Fold Modifier1 (UFM1) applied to substrate proteins. Blazev et al. develop an antibody-based enrichment approach followed by LC-MS/MS to ...

This article studies the role of UFMylation in NLRP3 inflammasome activation. It reveals that UFMylation, mediated by the E3 Ufm1-ligase 1 (Ufl1), maintains NLRP3 stability by preventing its ubiquiti....

The small ubiquitin-like modifier UFM1 is known to regulate the ribosomal subunit RPL26, but whether other bona fide substrates exist remains debated. This Comment discusses criteria for the experimen...

UFMylation is the post-translational modification of Ubiquitin Fold Modifier1 (UFM1) applied to substrate proteins. Blazev et al. develop an antibody-based enrichment approach followed by LC-MS/MS to ...

Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation defic...

Cells rely on DNA repair to maintain genome stability. Here, the authors show that the ubiquitin-like modifier UFM1 directs non-homologous end-joining by modifying Ku70, recognised by XRCC4 to promote repair complex assembly, linking defective UFMylation to impaired DNA repair in patient cells.

Read the full paper: The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis

Ufmylation is a recently identified small ubiquitin-like modification, whose biological function and relevant cellular targets are poorly understood. Here we present evidence of a neuroprotective role for Ufmylation involving Autophagy-related gene 9 (Atg9) during Drosophila aging. The Ufm1 system ensures the health of aged neurons via Atg9 by coordinating autophagy and mTORC1, and maintaining mitochondrial homeostasis and JNK (c-Jun N-terminal kinase) activity. Neuron-specific expression of Atg9 suppresses the age-associated movement defect and lethality caused by loss of Ufmylation. Furthermore, Atg9 is identified as a conserved target of Ufm1 conjugation mediated by Ddrgk1, a critical regulator of Ufmylation. Mammalian Ddrgk1 was shown to be indispensable for the stability of endogenous Atg9A protein in mouse embryonic fibroblast (MEF) cells. Taken together, our findings might have important implications for neurodegenerative diseases in mammals.

Nature Reviews Molecular Cell Biology, Published online: 16 February 2026; doi:10.1038/s41580-026-00951-7The small ubiquitin-like modifier UFM1 is known to regulate the ribosomal subunit RPL26, but whether other bona fide substrates exist remains debated. This Comment discusses criteria for the experimental validation of UFM1 substrates.

Nature Reviews Molecular Cell Biology, Published online: 16 February 2026; doi:10.1038/s41580-026-00951-7The small ubiquitin-like modifier UFM1 is known to regulate the ribosomal subunit RPL26, but whether other bona fide substrates exist remains debated. This Comment discusses criteria for the experimental validation of UFM1 substrates.

Nature Reviews Molecular Cell Biology, Published online: 09 January 2026; doi:10.1038/s41580-025-00944-yUFMylation, a ubiquitin-like modification, regulates endoplasmic reticulum-associated ribosome quality control by conjugating UFM1 to the ribosomal subunit RPL26, preserving ribosome integrity under stress. This Review explores the structural basis of UFMylation and its emerging functional breadth, and it discusses putative UFMylation substrates.