ISG15 suppresses ovulation and female fertility by ISGylating ADAMTS1

  • Cell Biosci. 2023 May 11;13(1):84. doi: 10.1186/s13578-023-01024-4.
Yaru Chen  1 ,  Jiawei Zhou  2  3 ,  Shang Wu  1 ,  Lei Wang  1 ,  Gaogui Chen  1 ,  Dake Chen  1 ,  Xianwen Peng  4 ,  Yi-Liang Miao  1 ,  Shuqi Mei  4 ,  Fenge Li  5  6
Affiliations
  • 1. Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China.
  • 2. Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China. [email protected].
  • 3. Institute of Animal Science and Veterinary Medicine, Hubei Academy of Agricultural Sciences, Wuhan, 430064, China. [email protected].
  • 4. Institute of Animal Science and Veterinary Medicine, Hubei Academy of Agricultural Sciences, Wuhan, 430064, China.
  • 5. Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China. [email protected].
  • 6. The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China. [email protected].
PMID: 37170317 DOI: 10.1186/s13578-023-01024-4
Abstract

Background: ISGylation is a post-translational protein modification that regulates many life activities, including immunomodulation, Antiviral responses, and embryo implantation. The exact contribution of ISGylation to folliculogenesis remains largely undefined.

Results: Here, Isg15 knockout in mice causes hyperfertility along with sensitive ovarian responses to gonadotropin, such as increases in cumulus expansion and ovulation rate. Moreover, ISG15 represses the expression of ovulation-related genes in an ISGylation-dependent manner. Mechanistically, ISG15 binds to ADAMTS1 via the ISG15-conjugating system (UBA7, UBE2L6, and HERC6), ISGylating ADAMTS1 at the binding sites Lys309, Lys593, Lys597, and Lys602, resulting in ADAMTS1 degradation via a 20S proteasome-dependent pathway.

Conclusion: Taken together, the present study demonstrates that covalent ISG15 conjugation produces a novel regulatory axis of ISG15-ADAMTS1 that enhances the degradation of ADAMTS1, thereby compromising ovulation and female fertility.

Keywords
ADAMTS1; Female fertility; ISGylation; Interferon-stimulated gene 15; Mice; Ovulation.
Products