Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity

Garrison Komaniecki, Maria Del Carmen Camarena, Eric Gelsleichter, Rachel Mendoza, Mark Subler, Jolene J. Windle, Mikhail G. Dozmorov, Zhao Lai, Devanand Sarkar, Hening Lin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)543-553
Number of pages11
JournalBiochemistry
Volume62
Issue number2
DOIs
StatePublished - Jan 17 2023

ASJC Scopus subject areas

  • Biochemistry

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