Key result
ARMC5 acts as a substrate adaptor protein between full-length SREBF and CUL3-based E3 ligase to induce SREBF degradation, a tumor-suppressor function that is lost in BMAH mutations.
Why the study?
Although ARMC5 inactivating mutations cause bilateral macronodular adrenal hyperplasia and ARMC5 is considered a tumor-suppressor gene, its molecular function is poorly understood.
ARMC5 functions as a substrate adaptor for CUL3-based E3 ligase to degrade SREBF, suggesting the SREBF pathway is involved in the development of bilateral macronodular adrenal hyperplasia.
Answers are grounded in this paper and cite their sources.
Does not yet inform BMAH management; leaves open SREBF pathway as hypothesis-generating therapeutic target.
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.
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Okuno et al. (2022) studied Bilateral macronodular adrenal hyperplasia (BMAH). ARMC5 was evaluated on SREBF degradation and cell growth. ARMC5 acts as a substrate adaptor protein between full-length SREBF and CUL3-based E3 ligase to induce SREBF degradation, a tumor-suppressor function that is lost in BMAH mutations.
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