ECE2022 Oral Communications Oral Communications 2: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)
Loss of SUMO-specific protease 2 leads to adrenal insufficiency limited to glucocorticoids
Damien Dufour 1 , Typhanie Dumontet 2 , Isabelle Sahut-Barnola 1 , Meline Onzon 1 , Eric Pussard 3 , James Wilmouth Jr 1 , Julie Olabe 1 , Adrien Levasseur 1 , Guillaume Bossis 4 , Edward Yeh 5 , Pierre Val 1 , Antoine Martinez 1 & Lefrançois-Martinez Anne-Marie 1
1CRBC (Centre de Recherche Bio Clinique), GReD, Clermont-Ferrand, France; 2Rogel Cancer Center, Ann Arbor, United States; 3Bicetre Hospital, Le Kremlin-Bicêtre, France; 4Institute of Molecular Genetics of Montpellier, Montpellier, France; 5University of Missouri, Columbia, United States
The adrenal gland produces corticosteroids essential for hydromineral and metabolic homeostasis. It is organised, in mice, in two concentric layers. The zona glomerulosa (zG) and fasciculate (zF), renewed from progenitors located in the capsular periphery. Centripetal renewal and maintenance of cortical zonation are dependant of a balance between WNT/β-catenin and ACTH/PKA signalling pathways. They provide recruitment and consecutive differentiation of progenitors into zG and zF. SUMOylation is a reversible post-translational modification mandatory for embryonic development. It consists of the serial reactions of activation, conjugation and ligation that will enables SUMOylation of a specific target protein. The presence of deSUMOylases mainly represented by SENPs makes SUMOylation particularly dynamic. In the adrenal cortex, it follows a centripetal decreasing gradient whose function is unknown. Moreover, chronic and acute PKA signalling stimulation leads to a decrease in SUMOyaltion in the adrenal cortex. In order to study the impact of hyperSUMOylation in the adrenal differentiation, we have chosen to delete the deSUMOylase SENP2 since it is positively regulated by ACTH/PKA signalling. Hence, we developed a model of Senp2 deficiency targeting specifically the adrenal cortex thanks to cre/loxP technology. Senp2 loss induces, as soon as 4 weeks of age, a glucocorticoids deficiency caused by zF hypoplasia without any defect in zG physiology. Even though, mice manage to normalise glucocorticoid levels throughout time, they still fail to respond properly to ACTH stimulation. We demonstrate, by biochemical and genetic experiments, that this lack of response was neither due to signalling upstream of PKA nor downstream, pointing toward a direct change in intrinsic PKA catalytic activity. The hypoplasia is associated with a stimulation of apoptosis at the zG/zF boundary. We show that this apoptosis was linked to a lack of PKA dependant phosphorylation of DRP1, whose phosphorylation state can induce either apoptosis or steroidogenesis. Finally, β-catenin, which is supposed to be limited to zG cell membrane, is found in the zF nuclei in Senp2 mutant adrenals. Moreover, this is associated with an increase in SUMOylation of β-catenin and mild activation of the WNT signalling pathway. In conclusion, we show that HyperSUMOylation affects zF homeostatic renewal by altering the balance between ACTH/PKA and WNT/β-catenin signalling pathways and by stimulating early apoptosis of the zF cells. SUMOylation is a central mechanism of adaptive cellular responses to stress. Our results suggest that it is a fundamental pathway in the processes of functional maintenance of the adrenal cortex.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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