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  4. Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function

Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function

Journal PLoS Genet. 17(8):e1009688 (2021)
Title Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function
Laboratory Laboratory of Intracellular Membrane Dynamics
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.

Authors

Tadashi Yamamuro (1), Shuhei Nakamura (1, 2, 3), Yu Yamano (2), Tsutomu Endo (4), Kyosuke Yanagawa (1, 5), Ayaka Tokumura (1), Takafumi Matsumura (4), Kiyonori Kobayashi (4), Heto Mori (6, 7), Yusuke Enokani (1), Gota Yosha (1), Hitomi Imoto (1, 2), Tsuyoshi Kawabata (1, 2, 8), Maho Hamasaki (1, 2), Akiko Kuma (1, 2), Sohei Kuribayashi (9), Kentaro Takezawa (9), Yuki Okada (10), Manabu Ozawa (11), Shinichiro Fukuhara (9), Takashi Shinohara (12), Masahito Ikawa (4, 11), Tamotsu Yoshimori (1, 2, 13)

  1. Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
  2. Laboratory of Intracellular Membrane Dynamics, Graduate school of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
  3. Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, Japan
  4. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
  5. Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
  6. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
  7. Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa, Japan
  8. Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Nagasaki, Japan
  9. Department of Urology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
  10. Laboratory of Pathology and Development, The Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan
  11. Laboratory of Reproductive Systems Biology, The Institute of Medical Science, The University of Tokyo, Minato-Ku, Tokyo, Japan
  12. Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto, Japan
  13. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan
PubMed 34351902

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