オオツキ　ミチオ   Ootsuki Michio   大月　道夫    所属   医学部 医学科（東京女子医科大学病院）    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocortical tumors.
掲載誌名	正式名：JCI insight 略　 称：JCI Insight ISSNコード：23793708/23793708
掲載区分	国外
巻・号・頁	7(16),pp.e151390
著者・共著者	Okuno Yosuke, Fukuhara Atsunori, Otsuki Michio, Shimomura Iichiro
発行年月	2022/08
概要	Inactivating mutations of ARMC5 are responsible for the development of bilateral macronodular adrenal hyperplasia (BMAH). Although ARMC5 inhibits adrenocortical tumor growth and is considered a tumor-suppressor gene, its molecular function is poorly understood. In this study, through biochemical purification using SREBF (SREBP) as bait, we identified the interaction between SREBF and ARMC5 through its Armadillo repeat. We also found that ARMC5 interacted with CUL3 through its BTB domain and underwent self-ubiquitination. ARMC5 colocalized with SREBF1 in the cytosol and induced proteasome-dependent degradation of full-length SREBF through ubiquitination. Introduction of missense mutations in Armadillo repeat of ARMC5 attenuated the interaction between SREBF, and introduction of mutations found in BMAH completely abolished its ability to degrade full-length SREBF. In H295R adrenocortical cells, silencing of ARMC5 increased full-length SREBFs and upregulated SREBF2 target genes. siARMC5-mediated cell growth was abrogated by simultaneous knockdown of SREBF2 in H295R cells. Our results demonstrate that ARMC5 was a substrate adaptor protein between full-length SREBF and CUL3-based E3 ligase, and they suggest the involvement of the SREBF pathway in the development of BMAH.
DOI	10.1172/jci.insight.151390
PMID	35862218