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UFMylation anchors splicing factors at the ER to reprogram nuclear splicing

ABSTRACT: How organelles communicate stress to the nucleus to coordinate adaptive responses remains a fundamental question in cell biology. Here, we identify a non-canonical retrograde signaling pathway in which stalling-induced UFMylation of ER-associated ribosomes anchors splicing regulators at the ER, directly coupling translational stress to nuclear RNA processing. Phylogenetic profiling linked the UFMylation machinery to a network of nuclear mRNA processing factors. Fractionation-based quantitative proteomics revealed that translational stress triggers UFM1-dependent retention of serine/arginine-rich (SR) splicing factors at the ER, depleting their nuclear pools. Mechanistically, UFMylated ribosomes physically tether SR proteins at the ER surface, driving widespread intron retention that preferentially targets transcripts encoding ER membrane and trafficking components—a response conserved from plants to mammals. These findings reframe UFMylation from a local ribosome repair signal to a systems-level coordinator of ER-nucleus communication that reprograms nuclear splicing and reshapes membrane-associated gene expression with implications for neurodegenerative diseases linked to UFMylation defects.

ORGANISM(S): Mus musculus Arabidopsis thaliana Homo sapiens

PROVIDER: GSE325905 | GEO | 2026/03/27

REPOSITORIES: GEO

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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.

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UFMylation anchors splicing factors at the ER to reprogram nuclear splicing

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