2. Academic Validation
  3. P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

  • Cell Mol Life Sci. 2024 May 20;81(1):221. doi: 10.1007/s00018-024-05251-x.
Ting Zhao # 1,  Meina He # 2,  Zijian Zhu 1,  Tuo Zhang 3,  Wenying Zheng 1,  Shaogang Qin 1,  Meng Gao 1,  Wenji Wang 4,  Ziqi Chen 1,  Jun Han 1,  Longping Liu 5,  Bo Zhou 1,  Haibin Wang 6,  Hua Zhang 1,  Guoliang Xia 1 7,  Jianbin Wang 5,  Fengchao Wang 8,  Chao Wang 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
  • 2 College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, 550025, China.
  • 3 Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, 550025, China.
  • 4 School of Life Science, Taizhou University, Taizhou, 318000, China.
  • 5 School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 6 Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian Province, 361005, China.
  • 7 Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, College of Life Science, Ningxia University, Yinchuan, 750021, China.
  • 8 Transgenic Animal Center, National Institute of Biological Sciences, Beijing, 102206, China.
  • 9 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. wangcam@126.com.
  • 10 China Agricultural University, No.2 Yuan Ming Yuan West Road, Haidian District, Beijing, 100193, China. wangcam@126.com.
  • # Contributed equally.
PMID: 38763964 DOI: 10.1007/s00018-024-05251-x
Abstract

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective Autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome Sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.

Keywords

Antral follicles formation; FSH; Granulosa cell differentiation; Ubiquitinatized WT1; p62.

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