{"doi":"10.1016/j.jbc.2023.105346","title":"SARS-CoV-2 papain-like protease plays multiple roles in regulating cellular proteins in the endoplasmic reticulum","abstract":"Nsp3s are the largest nonstructural proteins of coronaviruses. These transmembrane proteins include papain-like proteases (PLpro) that play essential roles in cleaving viral polyproteins into their mature units. The PLpro of SARS-CoV viruses also have deubiquitinating and deISGylating activities. As Nsp3 is an endoplasmic reticulum (ER)-localized protein, we asked if the deubiquitinating activity of SARS-CoV-2 PLpro affects proteins that are substrates for ER-associated degradation (ERAD). Using full-length Nsp3 as well as a truncated transmembrane form we interrogated, by coexpression, three potential ERAD substrates, all of which play roles in regulating lipid biosynthesis. Transmembrane PLpro increases the level of INSIG-1 and decreases its ubiquitination. However, different effects were seen with SREBP-1 and SREBP-2. Transmembrane PLpro cleaves SREBP-1 at three sites, including two noncanonical sites in the N-terminal half of the protein, resulting in a decrease in precursors of the active transcription factor. Conversely, cleavage of SREBP-2 occurs at a single canonical site that disrupts a C-terminal degron, resulting in increased SREBP-2 levels. When this site is mutated and the degron can no longer be interrupted, SREBP-2 is still stabilized by transmembrane PLpro, which correlates with a decrease in SREBP-2 ubiquitination. All of these observations are dependent on PLpro catalytic activity. Our findings demonstrate that, when anchored to the ER membrane, SARS-CoV-2 Nsp3 PLpro can function as a deubiquitinating enzyme to stabilize ERAD substrates. Additionally, SARS-CoV-2 Nsp3 PLpro can cleave ER-resident proteins, including at sites that could escape analyses based on the established consensus sequence.","journal":"Journal of Biological Chemistry","year":2023,"id":353119,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":723051,"name":"Jennifer Mariano","orcid":"0000-0002-2087-9388","position":1,"is_corresponding":false},{"id":1099339,"name":"R. Su","orcid":"0009-0000-2390-4342","position":2,"is_corresponding":false},{"id":723050,"name":"Christopher E. Smith","orcid":"0000-0003-0820-0341","position":3,"is_corresponding":false},{"id":276004,"name":"Sudipto Das","orcid":"0009-0000-8325-0088","position":4,"is_corresponding":false},{"id":1099340,"name":"Catherine Gill","orcid":"0009-0009-8949-4265","position":5,"is_corresponding":false},{"id":276014,"name":"Þorkell Andrésson","orcid":"0000-0002-9545-2450","position":6,"is_corresponding":false},{"id":304001,"name":"Jadranka Lončarek","orcid":"0000-0003-1879-5473","position":7,"is_corresponding":false},{"id":283914,"name":"Yien Che Tsai","orcid":"0000-0001-9624-1092","position":8,"is_corresponding":false},{"id":283915,"name":"Allan M. Weissman","orcid":"0000-0002-7865-7702","position":9,"is_corresponding":false},{"id":947184,"name":"Mei Yang","orcid":"0000-0003-2111-2354","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:12:58.542950Z","pmid":"37838170","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}