THE LIFE CYCLE OF THE STEROIDOGENIC ACUTE REGULATORY (StAR) PROTEIN: FROM TRANSCRIPTION THROUGH PROTEOLYSIS

Abstract

The Steroidogenic Acute Regulatory (StAR) protein is a mitochondrial protein required for the transport of cholesterol substrate to the P450scc enzyme located in the inner mitochondrial membranes of steroid producing cells. This study suggests that the acute regulation of the rodent StAR gene in the ovary is mediated by two factors, C/EBPbeta and GATA-4. Once translated, the StAR precursor protein is either imported into the mitochondria, or it is rapidly degraded in the cytosol. We predicted that in order to perpetuate StAR activity cycles, imported StAR should turn over rapidly to avoid a potentially harmful accumulation of the protein in sub-mitochondrial compartments. Pulse-chase experiments in metabolically labeled cells showed that: (a) the turnover rate of mature mitochondrial StAR protein (30 kDa) is much faster (t(1/2) = 4-5 h) than that of other mitochondrial proteins; (b) dissipation of the inner membrane potential (-delta psi) by carbonyl cyanide m-chlorophenylhydrazone (mCCCP) accelerates the mitochondrial degradation of StAR; (c) unexpectedly, the mitochondrial degradation of StAR is inhibited by MG132 and lactacystin, but not by epoxomicin. Furthermore, StAR degradation becomes inhibitor-resistant two hours after import. Therefore, these studies suggest a bi-phasic route of StAR turnover in the mitochondria. Shortly after import, StAR is degraded by inhibitor-sensitive protease(s) (phase I), whereas at later times, StAR turnover proceeds to completion through an MG132-resistant proteolytic activity (phase II). Collectively, this study defines StAR as a unique protein that can authentically be used to probe multiple proteolytic activities in mammalian mitochondria.

Estradiol regulation of progesterone synthesis in the brain

“…The overall rate-limiting step of steroidogenesis is the transport of cholesterol from the outer to the inner mitochondrial membrane effected by steroid acute regulatory protein (StAR), peripheral-type benzodiazepine receptor (PBR) and its endogenous ligand, diazepam binding inhibitor (DBI; (Granot et al, 2002;Kallen et al, 1998;King et al, 2002;Stocco, 2001;Stocco and Clark, 1996) for reviews see (Niswender, 2002;Papadopoulos, 1993)). In the nervous system, StAR, PBR and DBI have been localized in astrocytes (Karri et al, 2007;Lamacz et al, 1996;Young, 1994).…”

StAR-related Lipid Transfer (START) Proteins: Mediators of Intracellular Lipid Metabolism

“…Therefore, the presequence may direct cholesterol transfer to mitochondria in preference to other organelles (15). In addition, import may rapidly inactivate StAR (21), as StAR undergoes proteolytic degradation in mitochondria (27).…”

Constitutive Steroidogenesis in Ovine Large Luteal Cells May Be Mediated by Tonically Active Protein Kinase A1

“…The treatment time (4 h) may have been too short to induce changes in the steady-state concentrations of STAR. In addition, the ELISA to quantify the concentrations of STAR protein predominantly quantifies the 30-kDa form of STAR due to its greater abundance, which is the result of its longer half-life relative to the 37-kDa form [30][31]. Any changes in expression of the STAR protein induced by the different treatments would likely be more apparent in the short-lived 37-kDa form.…”

“…4A) in all groups, except for the control. The predominant form of STAR was the 30-kDa form, probably because it had a 4-h halflife, compared to the 15-min half-life of the 37-kDa form [30].…”