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

Damien Dufour, Typhanie Dumontet, Isabelle Sahut-Barnola, Aude Carusi, Méline Onzon, Eric Pussard, James Jr Wilmouth, Julie Olabe, Cécily Lucas, Adrien Levasseur, Christelle Damon-Soubeyrand, Jean-Christophe Pointud, Florence Roucher-Boulez, Igor Tauveron, Guillaume Bossis, Edward T. Yeh, David T. Breault, Pierre Val, Anne-Marie Lefrançois-Martinez and Antoine Martinez ()
Additional contact information
Damien Dufour: Université Clermont Auvergne
Typhanie Dumontet: Université Clermont Auvergne
Isabelle Sahut-Barnola: Université Clermont Auvergne
Aude Carusi: CNRS
Méline Onzon: Université Clermont Auvergne
Eric Pussard: Université Paris-Saclay
James Jr Wilmouth: Université Clermont Auvergne
Julie Olabe: Université Clermont Auvergne
Cécily Lucas: Université Clermont Auvergne
Adrien Levasseur: Université Clermont Auvergne
Christelle Damon-Soubeyrand: Université Clermont Auvergne
Jean-Christophe Pointud: Université Clermont Auvergne
Florence Roucher-Boulez: Université Clermont Auvergne
Igor Tauveron: Université Clermont Auvergne
Guillaume Bossis: CNRS
Edward T. Yeh: University of Arkansas for Medical Sciences
David T. Breault: Harvard Medical School
Pierre Val: Université Clermont Auvergne
Anne-Marie Lefrançois-Martinez: Université Clermont Auvergne
Antoine Martinez: Université Clermont Auvergne

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35526-5

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