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Cited by 4614-3-3 protein interactionsSteroid Chemistry and BiochemistryEstrogen and related hormone effects

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

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Aghazadeh, Yasaman, Rone, Malena B., Blonder, Josip, Ye, Xiaoying, Veenstra, Timothy D., Hales, D. Buck, Culty, Martine, Papadopoulos, Vassilios·2012·Journal of Biological Chemistry
DOI 10.1074/jbc.m112.339580PMC PMC3346089
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Abstract

Cholesterol is the sole precursor of steroid hormones in the body. The import of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroid biosynthesis, relies on the formation of a protein complex that assembles at the outer mitochondrial membrane called the transduceosome. The transduceosome contains several mitochondrial and cytosolic components, including the steroidogenic acute regulatory protein (STAR). Human chorionic gonadotropin (hCG) induces de novo synthesis of STAR, a process shown to parallel maximal steroid production. In the hCG-dependent steroidogenic MA-10 mouse Leydig cell line, the 14-3-3γ protein was identified in native mitochondrial complexes by mass spectrometry and immunoblotting, and its levels increased in response to hCG treatment. The 14-3-3 proteins bind and regulate the activity of many proteins, acting via target protein activation, modification and localization. In MA-10 cells, cAMP induces 14-3-3γ expression parallel to STAR expression. Silencing of 14-3-3γ expression potentiates hormone-induced steroidogenesis. Binding motifs of 14-3-3γ were identified in components of the transduceosome, including STAR. Immunoprecipitation studies demonstrate a hormone-dependent interaction between 14-3-3γ and STAR that coincides with reduced 14-3-3γ homodimerization. The binding site of 14-3-3γ on STAR was identified to be Ser-194 in the STAR-related sterol binding lipid transfer (START) domain, the site phosphorylated in response to hCG. Taken together, these results demonstrate that 14-3-3γ negatively regulates steroidogenesis by binding to Ser-194 of STAR, thus keeping STAR in an unfolded state, unable to induce maximal steroidogenesis. Over time 14-3-3γ homodimerizes and dissociates from STAR, allowing this protein to induce maximal mitochondrial steroid formation.

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  • Functional partners of the transduceosome include mitochondria-associated members of the 14-3-3 adaptor protein family and kinase signalers such as ERK1/2.

    “In addition, functional partners of the transduceosome have been identified, including mitochondria-associated members of the 14-3-3 adaptor protein family (92, 93) as well as kinase signalers such as extracellular signal-regulated kinase (ERK) 1/2 (94);”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [92]

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Metadata

Authors
Aghazadeh, Y., Rone, M. B., Blonder, J., Ye, X., Veenstra, T. D., Hales, D. B., Culty, M., & Papadopoulos, V.
Affiliations
  • Research Institute of the McGill University Health Centre (CA)
  • National Institutes of Health (US)
  • Southern Illinois University Carbondale (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2012-05
Volume
287
Issue
19
Pages
15380-15394
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m112.339580
PMC
PMC3346089
OpenAlex
W2102736458
Cited by
46
References
14
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 3 · 2015: 9 · 2014: 4 · 2013: 1 · 2012: 1
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
Funders
Canadian Institutes of Health Research (MOP102647)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
  • Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Keywords
14-3-3γ, steroidogenic acute regulatory protein, stars, steroidogenesis, MA-10 Leydig cells, human chorionic gonadotropin, cAMP signaling, START domain, protein homodimerization, protein-protein interaction
MeSH terms
Steroidogenic Acute Regulatory Protein, Cyclic AMP, Amino Acid Sequence, Animals, Binding Sites, Chorionic Gonadotropin, Leydig Cells, Male, Mitochondria, Molecular Sequence Data, Phosphoproteins, Protein Binding, Serine, Mass Spectrometry, Steroids, Testis, Immunoblotting, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Immunoprecipitation, 14-3-3 Proteins, Mice

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