biostudies-literatureChen YHubei Agricultural Science and Technology Innovation Action ProjectJiangsu Provincial Key Research and Development ProgramScience and Technology Service Network PlanTrans-gene Key Project of ChinaKey Technologies Research and Development Program of Anhui Province84https://www.ebi.ac.uk/biostudies/studies/S-EPMC10176748biostudies-literatureUnknown13(1)<h4>Background</h4>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.<h4>Results</h4>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 pathwaCell & bioscienceISG15 suppresses ovulation and female fertility by ISGylating ADAMTS1.PMC101767482018skjcx052018ZX08009-27B2021YFF10006012020BBB0692020ABA016Peng XLi FWu SChen GMei SChen YZhou JWang LChen DMiao YLfalseISG15 suppresses ovulation and female fertility by ISGylating ADAMTS1.<h4>Background</h4>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.<h4>Results</h4>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 pathwa2023-01-01T00:00:00Z2023 May2025-04-26T17:21:00.442Z2025-04-06T15:32:05.128ZS-EPMC101767483717031710.1186/s13578-023-01024-4