Endocrine Abstracts

Pathogenic ARMC5 variants are the main genetic cause of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) explaining roughly 20% of index cases. These variants found both at germline and somatic level are mostly frameshift and nonsense leading to a loss of its function. ARMC5 acts then, as a tumor suppressor gene but little was initially known on its function. Using an RNAseq analysis on transient zebrafish models of Armc5 up- and down-regulation, we identified transcriptional alterations of several members of SIRT1 signaling in our models suggesting that ARMC5 may regulate the desacetylase SIRT1 and its signaling in adrenocortical cells. Consistently, there is a significant increase of SIRT1 protein in PBMAH tissues mutated for ARMC5 compared to PBMAH without known genetic alterations. Interestingly, we show that ARMC5 interacts with SIRT1 in the H295R human adrenocortical cells and that ARMC5 knockdown leads to a decrease of SIRT1 ubiquitination. These results are consistent with 2022 reports demonstrating that ARMC5 acts as a protein adaptor for Cullin 3 complex, recruiting protein substrate to be ubiquitinated by this complex in order to lead to their proteosomal degradation. We speculate that SIRT1 could be a new protein substrate for the Cullin3-ARMC5 complex. While we analyze the global protein acethylation profile in PBMAH tissues, we observe an elevation of acetylated protein in absence of ARMC5 suggesting either a global reduction of protein desacethylation or increase of acethylation. To access more specifically the potential consequence of ARMC5 loss on SIRT1 activity, we measure SIRT activity and demonstrate a decrease of its activity in PBMAH mutated for ARMC5 as well as in adrenal cells of 18-month-old Armc5^+/- mice presenting an elevation of plasma corticosterone level. The decrease of SIRT1 activity leading to an abnormal protein acetylation could then, play a role in the development of PBMAH and in the cortisol hypersecretion. Altogether, these data support that ARMC5 could regulate SIRT1 protein accumulation (possibly through the Cullin3 complex) but could also regulate its activity by a mechanism that remains to be determined.