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

Abstract

Mutations in the <i>PRKACA</i> gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing's syndrome. <i>PRKACA</i> encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that <i>PRKACA</i> mutations lead to impairment of regulatory (R) subunit binding. Furthermore, <i>PRKACA</i> 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 <i>PRKACA</i> 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 <i>PRKACA</i> mutations, adding another dimension to the deregulation of PKA signaling caused by <i>PRKACA</i> mutations in adrenal Cushing's syndrome.