Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis.

TitleCell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsYin Y, Liu L, Yang C, Lin C, Veith GMichael, Wang C, Sutovsky P, Zhou P, Ma L
JournalJ Biol Chem
Volume291
Issue13
Pagination6923-35
Date Published2016 Mar 25
ISSN1083-351X
KeywordsAdenosine Triphosphate, Animals, Axoneme, Cullin Proteins, Gene Deletion, Gene Expression Regulation, Infertility, Male, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Microtubules, Proteolysis, Signal Transduction, Sperm Count, Sperm Motility, Spermatogenesis, Spermatozoa, Stem Cell Niche, Ubiquitin-Protein Ligases, Ubiquitination
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.

DOI10.1074/jbc.M115.699660
Alternate JournalJ Biol Chem
PubMed ID26846852
PubMed Central IDPMC4807277
Grant ListR01 ES016597 / ES / NIEHS NIH HHS / United States
1R01 CA159925 / CA / NCI NIH HHS / United States
1R01 CA098210 / CA / NCI NIH HHS / United States
P30 CA091842 / CA / NCI NIH HHS / United States
P30CA91842 / CA / NCI NIH HHS / United States
ES016597 / ES / NIEHS NIH HHS / United States
R01 CA098210 / CA / NCI NIH HHS / United States
R01 CA159925 / CA / NCI NIH HHS / United States
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