Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice

Abstract

SUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by Adrenocorticotropic Hormone (ACTH)/cAMP-dependent Protein Kinase (PKA) signalling within the zonafasciculata, we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zona fasciculata, a blunted reponse to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/β-catenin signalling leading to repression of PKA activity and ectopic activation of β-catenin. At the cellular level, this blocks transdifferentiation of β-catenin-positive zona glomerulosa cells into fasciculata cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness.

Loss of FUT8 in renal tubules ameliorates ischemia‐reperfusion injury‐induced renal interstitial inflammation transition to fibrosis via the TLR3–NF‐κB pathway

“…[10][11][12] However, increasing data suggest that posttranslational modifications mediate regulation of protein function, which may be independent of protein expression level in some pathophysiological processes. [13][14][15] Therefore, such modifications could be crucial regulators of protein function. Glycosylation is one of the most important post-translational protein and lipid modifications, where cell surface glycoconjugates are thought to be important in various biological functions, including cell-cell and cell-substrate interactions, cell immunogenicity, and cell signaling.…”

“…Currently, inhibition of protein expression is a common scheme for abrogating protein function in certain diseases 10–12 . However, increasing data suggest that post‐translational modifications mediate regulation of protein function, which may be independent of protein expression level in some pathophysiological processes 13–15 . Therefore, such modifications could be crucial regulators of protein function.…”