Abstract
Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing's syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser114 phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing's syndrome.
Highlights
Cushing’s syndrome (CS), a severe condition characterized by endogenous cortisol excess, is associated with increased morbidity and mortality
Adrenocorticotropic hormone (ACTH)–independent CS is most often caused by benign cortisol-producing adrenal adenomas (CPAs), 30 to 67% of which carry activating mutations in the PRKACA gene encoding the catalytic subunit of protein kinase A (PKA) [1,2,3,4]
These results suggest that specific L206R activity leads to R subunit II (RII) degradation and that 8-Br-cyclic adenosine 5′-monophosphate (cAMP) activates the endogenous, WT PKA that protects RII from degradation in the presence of the L206R mutant
Summary
Cushing’s syndrome (CS), a severe condition characterized by endogenous cortisol excess, is associated with increased morbidity and mortality. In its inactive form, PKA is a heterotetramer that consists of two catalytic (C) and two regulatory (R) subunits [5] Both catalytic and regulatory subunits exist in several isoforms, three catalytic ( , , and ) and four regulatory (I , I , II , and II ) subunit isoforms, each encoded by a separate gene [6] and expressed differentially throughout tissues [7]. R subunits confer differential localization of the tetrameric complex to different subcellular compartments. The latter is achieved via interaction with a family of scaffolding proteins known as A-kinase anchoring proteins (AKAPs) [7]. Upon binding of cAMP, the R subunits undergo a conformational change that reduces their affinity for C subunits, leading to the release and activation of the C subunits [9]
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