JOSD2 promotes non-small cell lung cancer proliferation by removing K6-linked polyubiquitination from LKB1
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ABSTRACT:
PROVIDER: PRJNA814993 | ENA |
REPOSITORIES: ENA
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Project description:Deubiquitinating enzymes (DUBs), frequently overactivated in cancers, are associated with tumorigenesis and regarded as promising therapeutic targets. However, the tumor-promoting role and underlying mechanism of DUBs in non-small cell lung cancer (NSCLC) are poorly understood. Through a global analysis of the contribution of 88 DUBs in NSCLC survival possibilities, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC tumor growth in vivo in both NCI-H1299-derived xenografts and patient-derived xenografts. Mechanistically, JOSD2 functioned as a DUB by removing K6-linked polyubiquitination from LKB1, which was critical for maintaining LKB1-STRAD-MO25 complex integrity and hence its kinase activity. Furthermore, for the first time, we identified small molecule inhibitor of JOSD2 and the pharmacological inhibition of JOSD2 significantly arrested NSCLC proliferation both in vitro and in vivo. Notably, our findings demonstrate a crucial role of JOSD2 in hindering LKB1 activity, highlighting JOSD2 as a potential therapeutic target in NSCLC and providing its inhibitors as a promising strategy for NSCLC treatment.
2024-01-10 | GSE198415 | GEO
Project description:Deubiquitinases (DUBs), frequently overactivated in cancers, are associated with tumorigenesis and regarded as promising therapeutic targets. However, the underlying mechanism of DUBs promoting non-small cell lung cancer (NSCLC) are poorly understood. Through a global analysis of the contribution of 97 DUBs in NSCLC survival possibilities by The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in vivo in both cell/patient-derived xenografts. Mechanistically, JOSD2 inhibits LKB1 kinase activity by removing K6-linked polyubiquitination, which was critical for maintaining LKB1-STRAD-MO25 complex integrity. Furthermore, we identified the first small molecule inhibitor of JOSD2 and the pharmacological inhibition of JOSD2 significantly arrested NSCLC proliferation in vitro/in vivo. Notably, our findings demonstrate a crucial role of JOSD2 in hindering LKB1 activity, highlighting JOSD2 as a potential therapeutic target in NSCLC and providing its inhibitors as a promising strategy for NSCLC treatment.
2024-01-26 | PXD046139 | Pride
Project description:Reactive aldehydes induce the formation of RNA-protein crosslinks (RPCs), RPCs in the mRNA stall the ribosome and inhibit translation, RPCs are K6-linked ubiqutylated by RBR-type E3 ligase RNF14, RPCs are resolved in a UBXN1-VCP/p97-dependent manner
2023-11-03 | GSE240625 | GEO
Project description:Reactive aldehydes are produced during cellular metabolism and can accumulate in specific tissues particularly when aldehyde clearance mechanisms are impaired. Reactive aldehydes induce DNA-DNA and DNA-protein crosslinks (DPCs) that are repaired by different DNA repair pathways. Cellular toxicity of endogenous formaldehyde has been attributed to the damage of the genomic DNA and consequent inhibition of transcription. However, whether damage to other cellular macromolecules and interference with additional metabolic processes contributes to formaldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces toxic RNA-protein crosslinks (RPCs) in mRNA that inhibit translation and induce a specific RPC stress response pathway that is characterized by linkage-specific ubiquitylation. RPCs in the mRNA are recognized by stalling ribosomes and marked by K6-linked ubiquitylation that promotes their clearance by the ubiquitin-dependent unfoldase VCP.
2023-09-01 | GSE225044 | GEO
Project description:TRAIP suppresses bladder cancer progression by catalyzing K48-linked polyubiquitination of MYC
| PRJNA993280 | ENA
Project description:Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.
| S-EPMC4283406 | biostudies-literature
Project description:K6-Linked Ubiquitylation Signals Reactive Aldehyde-Induced RNA-Protein Crosslink Resolution
| PRJNA1004331 | ENA
Project description:Atypical K6-linked ubiquitylation marks toxic RNA-protein crosslinks induced by formaldehyde
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Project description:VCP is an evolutionary conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.
2018-02-08 | GSE107313 | GEO
Project description:Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA–protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-Between-RING E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.
2023-11-13 | PXD038655 | Pride