Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD.
Spermatogenesis involves an early wave of germ cell apoptosis, which is required for maintaining the balance between germ cells and supporting Sertoli cells. However, the signaling mechanism regulating this apoptotic event is poorly defined. Here we show that genetic deficiency of Cyld, a recently identified deubiquitinating enzyme, attenuates the early wave of germ cell apoptosis and causes impaired spermatogenesis in mice. Interestingly, the loss of CYLD in testicular cells leads to activation of the transcription factor NF-kappaB and aberrant expression of antiapoptotic genes. We further show that CYLD negatively regulates a ubiquitin-dependent NF-kappaB activator, RIP1. CYLD binds to RIP1 and inhibits its ubiquitination and signaling function. These findings establish CYLD as a pivotal deubiquitinating enzyme (DUB) that regulates germ cell apoptosis and spermatogenesis and suggest an essential role for CYLD in controlling the RIP1/NF-kappaB signaling axis in testis.
Wright
Ato
A
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Reiley
William W
WW
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Chang
Mikyoung
M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Jin
Wei
W
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Lee
Andrew Joon
AJ
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Zhang
Minying
M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Sun
Shao-Cong
SC
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: ssun@mdanderson.org.
D000818:Animals; D017209:Apoptosis; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005854:Germ Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013091:Spermatogenesis; D054875:Ubiquitination
D020690:GTPase-Activating Proteins; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases