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Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining

ABSTRACT: As the most recently identified UBL, UFM1 is garnering increasing attention for its roles beyond its canonical functions at the endoplasmic reticulum. To address the challenge of defining UFM1 substrate-receptor relationships, we develop a fully functional, photo-crosslinkable UFM1 probe for receptor screening. The approach identifies a broad spectrum of UFM1-interacting proteins, spanning biological processes known to be regulated by UFM1 as well as unknown associations. Notably, several core NHEJ components ranked prominently amongst the candidates. Using additional biochemical and biophysical techniques, including crosslinking mass spectrometry (CX-MS), we validate and characterise non-canonical UFM1-binding regions on several NHEJ proteins, including XRCC4. In addition, using recombinant reagents, we have identified potential UFMylation sites of Ku70 and Ku80 through identification of VG-K remnant peptides following trypsin digestion.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Benjamin Foster

LAB HEAD: Christine Schmidt

PROVIDER: PXD069136 | Pride | 2026-06-25

REPOSITORIES: Pride

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			Action	DRS
	012624__BF_62248_C_5pc_01.raw	Raw
	012624__BF_62248_D_5pc_01.raw	Raw
	020724_BF_62332_A_NotXlinked_a.raw	Raw
	020724_BF_62332_A_NotXlinked_b.raw	Raw
	020724_BF_62332_A_NotXlinked_c.raw	Raw

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Project description:Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation-deficiencies cause selective neurological defects is unknown. Using Ufm1 knock-out mice, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the PERK-UPR pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81Cexpressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that the PERK-UPR inhibitor Trazodone restores protein translation solely in UFM1-R81C-expressing neurons, and increases synapse number. Our study unveils a pivotal role for UFMylation in neuronal development, provides a molecular understanding of the signaling mechanisms altered in UFM1- associated encephalopathies, and offers important insights into potential treatments for these Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation-deficiencies cause selective neurological defects is unknown. Using Ufm1 knock-out mice, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the PERK-UPR pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that the PERK-UPR inhibitor Trazodone restores protein translation solely in UFM1-R81C-expressing neurons, initiating an increase in synapse number. Our study unveils a pivotal role for UFMylation in neuronal development and provides a molecular understanding of the signaling mechanisms altered in UFM1-associated encephalopathies, offering valuable insights into potential treatments for these disorders.

Project description:Diatom-derived polyunsaturated aldehydes (PUAs) significantly influence marine bacterial dy-namics, yet the underlying proteomic mechanisms remain elusive. We employed high-resolution comparative proteomics to decipher the functional reprogramming of two bacterial communi-ties—one naturally associated with a PUA-producing diatom (N-community) and another with a non-PUA producer (I-community)—under ecologically relevant PUA exposure. While growth rates and cell densities remained unaffected, indicating an absence of acute toxicity, proteomics revealed pronounced community-specific reorganization. N-communities displayed stable, regula-tion-oriented adjustments consistent with physiological accommodation, whereas I-communities exhibited dose-dependent stress responses, shifting toward protein repair and antioxidant defense. Our findings demonstrate that PUAs trigger profound proteomic reprogramming conditioned by the communities' prior ecological history. This functional divergence provides a molecular basis for understanding bacterial fitness and succession during diatom blooms, where PUA-mediated in-teractions could act as a selective filter shaping the phycosphere's microbial landscape. Polyunsaturated aldehydes (PUA) produced by diatoms have been proposed to exert a wide range of effects on marine bacteria, from inhibitory or stress-inducing responses to neutral or potentially beneficial effects. However, the bacterial proteomic responses remain elusive. Here, we employed a high-resolution comparative proteomic approach to decipher the functional reprogramming of two distinct bacterial communities under ecologically relevant PUA exposure. One community was composed by bacteria naturally associated with a PUA-producing diatom (N- communy and, a second community associated with a non-PUA-producing diatom (I-community). Bacterial growth rates and final cell densities were not significantly affected by any treatment, indicating the absence of toxic effects even at high PUA concentrations. Dissolved organic carbon consumption did not provide evidence that PUA was the relevant carbon source. Interestingly, comparative proteomic analyses revealed pronounced community-specific reorganization in response to PUA expo-sure.Our results show that PUAs trigger a profound proteomic reprogramming rather than a simple stress response. While I-community prioritized antioxidant defense and protein repair, N-community showed a metabolic shift towards energy conservation. These findings suggest that the metabolic history of bacterial assemblages determines their success in the phycosphere, providing a molecular basis for microbial succession during diatom blooms.

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Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining

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