Michio Otsuki    Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine    Position   Professor and Division head
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocortical tumors.
Journal	Formal name：JCI insight Abbreviation：JCI Insight ISSN code：23793708/23793708
Domestic / Foregin	Foregin
Volume, Issue, Page	7(16),pp.e151390
Author and coauthor	Okuno Yosuke, Fukuhara Atsunori, Otsuki Michio, Shimomura Iichiro
Publication date	2022/08
Summary	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