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Transcriptional coactivator with PDZ‐binding motif suppresses the expression of steroidogenic enzymes by nuclear receptor 4 A1 in Leydig cells
Author(s) -
Shin Ji Hyun,
Lee Gibbeum,
Jeong Mi Gyeong,
Kim Hyo Kyeong,
Won Hee Yeon,
Choi Yujeong,
Lee JiHyeok,
Nam Miso,
Choi Cheol Soo,
Hwang GeumSook,
Hwang Eun Sook
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900695rrrr
Subject(s) - coactivator , nuclear receptor , pdz domain , microbiology and biotechnology , chemistry , steroidogenic factor 1 , enzyme , receptor , biology , transcription factor , biochemistry , gene
Transcriptional coactivator with PDZ‐binding motif (TAZ) plays crucial role in maintaining testicular structure and function via regulation of senescence of spermatogenic cells. However, it remains unclear whether TAZ is involved in testosterone biosynthesis in testicular Leydig cells. We found that TAZ deficiency caused aberrant Leydig cell expansion and increased lipid droplet formation, which was significantly associated with increased lipogenic enzyme expression. Additionally, the expression of key steroidogenic enzymes, including steroidogenic acute regulatory protein, cytochrome P450 (CYP) 11A1, CYP17A1, and 3β‐hydroxysteroid dehydrogenase, was greatly increased in TAZ‐deficient testes and primary Leydig cells. Interestingly, the transcriptional activity of nuclear receptor 4 A1 (NR4A1) was dramatically suppressed by TAZ; however, the protein expression and the subcellular localization of NR4A1 were not affected by TAZ. TAZ directly associated with the N‐terminal region of NR4A1 and substantially suppressed its DNA‐binding and transcriptional activities. Stable expression of TAZ in the mouse Leydig TM3 cell line decreased the expression of key steroidogenic enzymes, whereas knockdown of endogenous TAZ in TM3 cells increased transcripts of steroidogenic genes induced by NR4A1. Consistently, testosterone production was enhanced within TAZ‐deficient Leydig cells. However, TAZ deficiency resulted in decreased testosterone secretion caused by dysfunctional mitochondria and lysosomes. Therefore, TAZ plays essential role in NR4A1‐induced steroidogenic enzyme expression and testosterone production in Leydig cells.