{"doi":"10.1021/acs.biochem.2c00583","title":"Astrocyte Elevated Gene-1 Cys75 <i>S</i>-Palmitoylation by ZDHHC6 Regulates Its Biological Activity","abstract":"Nonalcoholic fatty liver disease is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments lipid accumulation (steatosis), inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for nonalcoholic steatohepatitis (NASH) and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue cysteine 75 (Cys75). Mutation of Cys75 to serine (Ser) completely abolished AEG-1 palmitoylation. We identified ZDHHC6 as a palmitoyltransferase catalyzing the process in HEK293T cells. To obtain insight into how palmitoylation regulates AEG-1 function, we generated knock-in mice by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation, angiogenesis, and lipid accumulation, were activated in AEG-1-C75S hepatocytes compared to AEG-1-WT. These findings suggest that AEG-1-C75S functions as dominant positive and that palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. We thus identify a previously unknown regulatory mechanism of AEG-1, which might help design new therapeutic strategies for NASH and HCC.","journal":"Biochemistry","year":2022,"id":269399,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":911799,"name":"Maria Del Carmen Camarena","orcid":null,"position":1,"is_corresponding":false},{"id":735109,"name":"Eric Gelsleichter","orcid":"0000-0002-5970-813X","position":2,"is_corresponding":false},{"id":911800,"name":"Rachel G. Mendoza","orcid":null,"position":3,"is_corresponding":false},{"id":330318,"name":"Mark A. Subler","orcid":null,"position":4,"is_corresponding":false},{"id":329122,"name":"Jolene J. Windle","orcid":"0000-0001-6690-385X","position":5,"is_corresponding":false},{"id":265858,"name":"Mikhail G. Dozmorov","orcid":"0000-0002-0086-8358","position":6,"is_corresponding":false},{"id":263243,"name":"Zhao Lai","orcid":"0000-0002-3543-5376","position":7,"is_corresponding":false},{"id":282002,"name":"Devanand Sarkar","orcid":"0000-0003-0973-2323","position":8,"is_corresponding":false},{"id":273804,"name":"Hening Lin","orcid":"0000-0002-0255-2701","position":9,"is_corresponding":false},{"id":277252,"name":"Garrison Komaniecki","orcid":"0000-0002-1157-2667","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:18.142851Z","pmid":"36548985","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":[]}