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UFMylation maintains translational homeostasis to ensure cell cycle progression

ABSTRACT: Cellular homeostasis is tightly linked to proliferation ensuring that only healthy cells divide. Homeostasis-sensing pathways including mTOR and integrated stress response (ISR) employ phosphorylation to regulate translation initiation and consequently cell cycle progression. Whether ubiquitin or ubiquitin-like molecules impact on translation and proliferation as part of existing or novel pathways is unknown. Here, we combine cell cycle screening, mass spectrometry and ribosome profiling to elucidate the molecular mechanism by which UFMylation, the modification of proteins with ubiquitin-fold modifier 1 molecules, controls translational homeostasis and cell cycle progression. Perturbation of UFMylation prevents eIF4F translation initiation complex assembly and recruitment of the ribosome. The ensuing global translational shutdown is sensed by cyclin D1 and halts the cell cycle independently of canonical ISR and mTOR signaling. Our findings establish UFMylation as a key regulator of translation that employs the principle of conserved cellular sensing mechanisms to couple translational homeostasis to cell cycle progression.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD015378 | Pride | 2022-03-23

REPOSITORIES: Pride

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			Action	DRS
	Fusion_JoergF_UFM1_8plex_P01.raw	Raw
	Fusion_JoergF_UFM1_8plex_P01R.raw	Raw
	Fusion_JoergF_UFM1_8plex_P02.raw	Raw
	Fusion_JoergF_UFM1_8plex_P02R.raw	Raw
	Fusion_JoergF_UFM1_8plex_P03.raw	Raw

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GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

Project description:Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of an individual tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant translational GTPases function in the same pathway to mitigate ribosome pausing. Ribosome stalling in the mutant brain led to activation of the integrated stress response (ISR) mediated by GCN2 and decreased mTORC1 signaling. However, in contrast to the ISR, which enhanced neuron survival, reduced mTORC1 signaling increased neuronal death. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective translation elongation.

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Project description:We recently identified ISRIB as a potent inhibitor of the integrated stress response (ISR). ISRIB renders cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents (10.7554/eLife.00498). Here we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2α and induced no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre-formed SGs induced their rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2α phosphorylation, SG formation and cognitive loss. Ribosome profiling with paired RNA-seq

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Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

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SAYSD1 senses UFMylated ribosome to safeguard co-translational protein translocation at the endoplasmic reticulum

Project description:Translocon clogging at the endoplasmic reticulum (ER) as a result of translation stalling triggers ribosome UFMylation, activating Translocation-Associated Quality Control (TAQC) to degrade clogged substrates. How cells sense ribosome UFMylation to initiate TAQC is unclear. We conduct a genome-wide CRISPR/Cas9 screen to identify an uncharacterized membrane protein named SAYSD1 that facilitates TAQC. SAYSD1 associates with the Sec61 translocon, and also recognizes both ribosome and UFM1 directly, engaging a stalled nascent chain to ensure its transport via the TRAPP complex to lysosomes for degradation. Like UFM1 deficiency, SAYSD1 depletion causes the accumulation of translocation-stalled proteins at the ER and triggers ER stress. Importantly, disrupting UFM1- and SAYSD1-dependent TAQC in Drosophila leads to intracellular accumulation of translocation-stalled collagens, defective collagen deposition, abnormal basement membranes, and reduced stress tolerance. Thus, SAYSD1 acts as a UFM1 sensor that collaborates with ribosome UFMylation at the site of clogged translocon, safeguarding ER homeostasis during animal development.

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ISR activation mediates the behavioral and neurophysiological abnormalities in Down syndrome

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Project description:In response to stress, eukaryotes activate the integrated stress response (ISR) via phosphorylation of eIF2α to promote the translation of pro-survival effector genes, such as GCN4 in yeast. Complementing the ISR is the Target of Rapamycin (TOR) pathway, which regulates eIF4E function. Here we probe translational control in the absence of eIF4E in Saccharomyces cerevisiae. Intriguingly, we find that loss of eIF4E leads to de-repression of GCN4 translation. In addition, we find that de-repression of GCN4 translation is neither accompanied by eIF2α phosphorylation nor reduction in initiator ternary complex. Our data suggest that when eIF4E levels are depleted, GCN4 translation is de-repressed via a unique mechanism that may involve faster scanning by the small ribosome subunit due to increased local concentration of eIF4A. Overall, our findings suggest that relative levels of eIF4F components are key to ribosome dynamics and may play important roles in translational control of gene expression.

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