Hormone-induced 14-3-3γ Adaptor Protein Regulates Steroidogenic Acute Regulatory Protein Activity and Steroid Biosynthesis in MA-10 Leydig Cells

Abstract

Background:The mechanism mediating hormone-induced steroidogenesis involves multiprotein complexes. Results: 14-3-3␥ is identified as a hormone-induced regulator of STAR function. Conclusion: 14-3-3␥ negatively regulates steroidogenesis by interacting with STAR, acting in a buffer capacity to sustain the STAR-mediated steroid formation for prolonged periods of time. Significance: Characterizing the mechanisms regulating steroidogenesis contributes to our understanding of how steroids are synthesized.

Protein Modifications Regulate the Role of 14-3-3γ Adaptor Protein in cAMP-induced Steroidogenesis in MA-10 Leydig Cells

“…STAR contains three suboptimal 14-3-3 motifs on critical structure sites and therefore binds 14-3-3␥ monomers with high affinity. 14-3-3␥ and STAR have similar transcription and translation profiles in MA-10 mouse Leydig tumor cells (26), and pre-existing mRNA encoding both proteins is translated upon treatment with the membrane-permeable cAMP analog 8-Br-cAMP. This compound is used to mimic endogenous cAMP, the secondary messenger of gonadotropin luteinizing hormone and the main activator of Leydig cell steroidogenesis.…”

“…Cholesterol is metabolized in the inner mitochondrial membrane by CYP11A1 to pregnenolone, the precursor of all steroids (26). It is at the transduceosome where the hormone-induced steroidogenic acute regulatory protein (STAR) accelerates cholesterol import into mitochondria (27).…”

“…It is at the transduceosome where the hormone-induced steroidogenic acute regulatory protein (STAR) accelerates cholesterol import into mitochondria (27). We recently reported that STAR is a target of the 14-3-3␥ isoform (26). STAR contains three suboptimal 14-3-3 motifs on critical structure sites and therefore binds 14-3-3␥ monomers with high affinity.…”

“…STAR phosphorylation at Ser 194 induces STAR activity by 2-fold, which is required for maximal steroidogenesis. Ser 194 mutations are one of the causes of congenital adrenal lipoid hyperplasia, a condition in which a lack of sufficient steroidogenesis causes cholesterol accumulation and adrenal cortex cells undergo hyperplasia and apoptosis (26). By locking phosphorylation of this site, 14-3-3␥ is able to retain STAR in the cytosol under basal activity, thus delaying its effect on mitochondrial steroidogenesis.…”

“…Phosphorylation can lead to self-dimerization (26) or interactions with specific targets (for a review, see Ref. 20).…”