Article Dans Une Revue Nature Communications Année : 2022

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

Typhanie Dumontet
  • Fonction : Auteur
Méline Onzon
  • Fonction : Auteur
Eric Pussard
  • Fonction : Auteur
Julie Olabe
Cécily Lucas
  • Fonction : Auteur
Adrien Levasseur
  • Fonction : Auteur
Christelle Damon-Soubeyrand
  • Fonction : Auteur
Florence Roucher-Boulez
Igor Tauveron
  • Fonction : Auteur
Guillaume Bossis
Edward Yeh
  • Fonction : Auteur
David Breault

Résumé

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 zona fasciculata , 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.
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hal-04255604 , version 1 (24-01-2025)

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Damien Dufour, Typhanie Dumontet, Isabelle Sahut-Barnola, Aude Carusi, Méline Onzon, et al.. Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice. Nature Communications, 2022, 13 (1), pp.7858. ⟨10.1038/s41467-022-35526-5⟩. ⟨hal-04255604⟩
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