{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE347nnn/GSE347660/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":["Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE347660"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Induced ubiquitination drives ER protein degradation through a VCP-dependent pathway","description":"Endoplasmic reticulum transmembrane (ER-TM) proteins are canonically degraded through ER-associated degradation (ERAD), which relies on membrane-embedded complexes for substrate recognition, ubiquitination, and extraction. To determine whether cytosolic E3 ligase-induced degradation of ER-TM proteins requires canonical ERAD machinery, we performed FACS-based CRISPR-Cas9 loss-of-function screens in reporter cell lines expressing topologically distinct ER-TM substrates using a degradation-focused sgRNA library targeting ubiquitin-proteasome, autophagy-lysosome, and ERAD pathway genes. Across all screens, the CUL2-VHL E3 ligase complex and neddylation machinery emerged as essential, consistent with their role in dTAGv-1-induced degradation. Strikingly, no canonical ERAD components, including substrate recognition factors, glycan-dependent lectins, or membrane-embedded dislocation complexes, were significantly enriched. Instead, VCP and its cofactors UFD1L and NPLOC4 emerged as critical factors for substrate extraction. These results support a VCP-dependent mechanism for cytosolic E3 ligase-induced degradation of ER-TM proteins that operates independently of canonical ERAD substrate processing machinery.","dates":{"publication":"2026/10/01"},"accession":"GSE347660","cross_references":{"GSM":["GSM10058268","GSM10058267","GSM10058269","GSM10058271","GSM10058270","GSM10058272"],"GPL":["30173"],"GSE":["347660"],"taxon":["Homo sapiens"]}}