Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Abstract

Testosterone is essential for spermatogenesis and the maintenance of secondary sexual characteristics in males. An important transcription factor, LIM-homeobox gene 9 (Lhx9) is indispensable for testis development and testosterone production; however, post-translational modifications of Lhx9 are largely unknown. Here, for the first time to our knowledge, we demonstrate that the level of Lhx9 protein increases in human chorionic gonadotropin-exposed Leydig cells and can be polyubiquitylated. We found that Smad ubiquitylation regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, targets Lhx9 for ubiquitin-mediated proteasome degradation, thereby negatively modulating its function. Increasing Smurf1 decreases the level of Lhx9 and inhibits the Lhx9 transactivation capacity of steroidogenic factor 1 [nuclear receptor subfamily 5, group A, member 1 (NR5A1)]. In contrast, the depletion of Smurf1 leads to increased expression of Lhx9 protein and enhances testosterone biosynthesis-related gene transcripts [NR5A1, steroidogenic acute regulatory protein, CYP17A1, hydroxy-δ-5-steroid dehydrogenase, hydroxy-δ-5-steroid dehydrogenase isomerase 6, and hydroxysteroid (17-β) dehydrogenase 3] and testosterone production in Leydig cells. Furthermore, we found that Smurf1 knockout mice exhibit higher levels of Lhx9 protein and steroidogenesis, which leads to increased serum testosterone concentration. These findings reveal that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly. Our results provide new insights into the molecular events that play a role in the homeostasis of testosterone levels and may provide a new target for testosterone regulation.-Hu, F., Zhu, Q., Sun, B., Cui, C., Li, C., Zhang, L. Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells.

Lhx9 haploinsufficiency alters transcription in the adult mouse ovary, causing subfertility and abnormal epithelium

“…If there is an altered differentiation of luteal cells in the Lhx9 +/ovary, this may impact the expression of cholesterol and steroidrelated genes. Lhx9 expression in the steroidal cells of the male Leydig cells has been shown previously 40,41 , thus the expression of Lhx9 shown here in the steroidal corporal lutea may reflect a function in the differentiation of steroidogenic cells.…”

Effects of 220 MHz Pulsed Modulated Radiofrequency Field on the Sperm Quality in Rats

“…Testosterone (T), a steroid hormone, produced mainly by LCs [26], is of vital importance to the development and function of male reproduction, and to the maintenance of normal spermatogenesis [27]. Shahin [10] reported that 1800 MHz RF exposure (1.15 W/m 2 , 3 h/day for 120 days) acted in the male reproductive tract of mice, in part by inhibiting T secretion from LCs.…”

Smurf1 aggravates non‐alcoholic fatty liver disease by stabilizing SREBP‐1c in an E3 activity‐independent manner

“…Smurf1 wild‐type and KO male mice were fed with a standard chow diet (CD) or high‐fat diet (HFD) (Research Diets, Cat# D12492 with 60 kcal% fat) for 19 weeks at the age of 4 weeks. Mice maintenance and HFD modeling were performed as described previously 15,16 . Mice feeding metabolism was analyzed using metabolic cages (TSE Systems GmbH, Bad Homburg, Germany).…”

“…Mice maintenance and HFD modeling were performed as described previously. 15,16 Mice feeding metabolism was analyzed using metabolic cages (TSE Systems GmbH, Bad Homburg, Germany). Mice were tested for 1 week and data from Days 5 to 7 were analyzed.…”