title: Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis.
abstract: CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation ofCul4ain mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4bgerm cell-specific conditional knock-out (Cul4b(Vasa)),as well asCul4bglobal knock-out (Cul4b(Sox2)) mouse, to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4bled to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility caused by reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore,Cul4b(Vasa)spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its direct polyubiquination and degradation by CUL4B E3 ligase. Nevertheless,Cul4bglobal knock-out males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell autonomously in male germ cells to ensure spermatozoa motility, whereas it functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis.
authors: From the Division of Dermatology, Department of Medicine and.
authors: Yan
authors: Y
authors: Yin
authors: the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and.
authors: Liren
authors: L
authors: Liu
authors: the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and.
authors: Chenyi
authors: C
authors: Yang
authors: From the Division of Dermatology, Department of Medicine and.
authors: Congxing
authors: C
authors: Lin
authors: From the Division of Dermatology, Department of Medicine and.
authors: George Michael
authors: GM
authors: Veith
authors: the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors: Caihong
authors: C
authors: Wang
authors: the Division of Animal Sciences and the Departments of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211.
authors: Peter
authors: P
authors: Sutovsky
authors: the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and.
authors: Pengbo
authors: P
authors: Zhou
authors: From the Division of Dermatology, Department of Medicine and lima@dom.wustl.edu.
authors: Liang
authors: L
authors: Ma
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D054468:Axoneme / Q000378:metabolism / Q000473:pathology; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction; D013076:Sperm Count; D013081:Sperm Motility; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology; D055153:Stem Cell Niche / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C524851:Cul4B protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; C512664:Insl6 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases
keywords: mouse genetics; protein degradation; spermatogenesis; ubiquitin; ubiquitin ligase