Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function

Abstract

Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell–related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.

Opposing roles of RUBCN isoforms in autophagy and memory B cell generation

“…On the basis of used gene-targeting strategies, only the mouse line used in this study was deficient in the expression of RUBCN 130 but not that of RUBCN 100 . Previous studies using this line have shown that RUBCN 130 deficiency in mouse models leads to enhanced autophagic flux in various cell types ( 12 , 14 , 15 , 17 , 18 ). However, the loss of both RUBCN isoforms does not enhance autophagic flux but rather impairs LAP/LANDO ( 19 , 20 , 22 ).…”

“…RUBCN deficiency in several cell types enhances autophagy and ameliorates nonalcoholic fatty liver, age-associated disorders such as interstitial fibrosis in the kidney, α-synuclein accumulation in the brain, systemic fat atrophy, osteoporosis, and myocardial ischemia/reperfusion injury (12)(13)(14)(15)(16). However, this deficiency induces metabolic syndrome (17) and suppresses Sertoli cell function (18) in mouse models. RUBCN also regulates a noncanonical autophagic process called LC-3-associated phagocytosis (LAP), LC-3-associated endocytosis (LANDO), or micropinocytosis (LAM) (19)(20)(21).…”

Single‐cell transcriptome analysis of the germ cells and somatic cells during mitotic quiescence stage in goats

“…In this study, we found that the changes in gene expression signatures were closely related to the function of specific cell types. For example, the expression of GATA4, a TF that is essential for Sertoli cell function, 70,71 was increased in Sertoli cells at E125. The expression of genes associated with sterol biosynthetic and metabolic processes, such as CYP11A1, STAR, and CYP51A1, was increased in Leydig cells at E125.…”

Rubicon in Metabolic Diseases and Ageing

“…A recent report has identified that Rubicon affects male fertility: Rubicon deficiency in Sertoli cells causes defective spermatogenesis via accelerated autophagic degradation of GATA4, which is an essential transcription factor for Sertoli cell function ( Yamamuro et al, 2021 ). This report is interesting from the viewpoint of ageing: it has been previously known that there is a negative correlation between fertility and longevity, although the causal relationship has been unclear ( Partridge et al, 2005 ; Kenyon, 2010 ).…”