The contribution of serine 194 phosphorylation to steroidogenic acute regulatory protein function

Goro Sasaki, Mohamad Zubair, Tomohiro Ishii, Toshikatsu Mitsui, Tomonobu Hasegawa, Richard J. Auchus

Research output: Contribution to journalArticle

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Abstract

The steroidogenic acute regulatory protein (StAR) facilitates the delivery of cholesterol to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme catalyzes the initial step of steroid hormone biosynthesis. StAR was initially identified in adrenocortical cells as a phosphoprotein, the expression and phosphorylation of which were stimulated by corticotropin. A number of in vitro studies have implicated cAMP-dependent phosphorylation at serine 194 (S194, S195 in human StAR) as an important residue for StAR activity. To explore the importance of S194 phosphorylation in StAR function in vivo, we developed a transgenic model using a bacterial artificial chromosome expressing either wild-type (WT) StAR or StAR mutation S194A to rescue StAR knockout (KO) mice. Despite StAR protein expression comparable to or higher than amounts seen with control animals or rescue with WT StAR, S194A StAR did not rescue the neonatal lethality and only partially rescued the sex reversal in male mice observed uniformly in StAR KO mice. Like the StAR KO mice, the adrenal cortex and testicular Leydig cells contained abundant lipid deposits when stained with oil red O. Adrenal StAR from S194A rescue animals lacks an acidic species, which appears upon corticotropin stimulation in animals rescued with WT StAR, consistent with defective StAR phosphorylation. These findings demonstrate that S194 is an essential residue for normal StAR function in the adrenal cortex and testes of mice.

Original languageEnglish
Pages (from-to)1088-1096
Number of pages9
JournalMolecular Endocrinology
Volume28
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Serine
Phosphorylation
Knockout Mice
steroidogenic acute regulatory protein
Adrenal Cortex
Adrenocorticotropic Hormone
Cholesterol Side-Chain Cleavage Enzyme
Bacterial Artificial Chromosomes
Leydig Cells
Phosphoproteins
Mitochondrial Membranes
Testis

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Medicine(all)

Cite this

The contribution of serine 194 phosphorylation to steroidogenic acute regulatory protein function. / Sasaki, Goro; Zubair, Mohamad; Ishii, Tomohiro; Mitsui, Toshikatsu; Hasegawa, Tomonobu; Auchus, Richard J.

In: Molecular Endocrinology, Vol. 28, No. 7, 2014, p. 1088-1096.

Research output: Contribution to journalArticle

Sasaki, Goro ; Zubair, Mohamad ; Ishii, Tomohiro ; Mitsui, Toshikatsu ; Hasegawa, Tomonobu ; Auchus, Richard J. / The contribution of serine 194 phosphorylation to steroidogenic acute regulatory protein function. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 7. pp. 1088-1096.
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