PKA C? subunit mutation triggers caspase-dependent RII? subunit degradation via Ser¹¹⁴ phosphorylation.

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 ? 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? protein levels; however, the mechanisms leading to reduced RII? 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 RII? is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RII? 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.

SUBMITTER: Weigand I 

PROVIDER: S-EPMC7895437 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature