PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser114 phosphorylation

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 alpha 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 RII beta protein levels; however, the mechanisms leading to reduced RII beta levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser(114) phosphorylation of RII beta is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RII beta 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.

Automated summary

Mutations in the PRKACA gene are a common cause of cortisol-producing adrenocortical adenomas and Cushing's syndrome, affecting the binding of regulatory subunits and leading to reduced RII β protein levels. The study shows that phosphorylation of RII β at Ser(114) is necessary for its degradation, mediated by caspase 16, resulting in increased cortisol secretion in adrenocortical cells. These findings provide insight into the molecular mechanisms and pathophysiological relevance of R subunit degradation caused by PRKACA mutations in adrenal Cushing's syndrome.