Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an "ancient" RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.

• Klíčová slova
• C-terminal degron, DCAF12, MOV10, T cell activation, WDR40A, spermatogenesis,
• MeSH
• aktivace lymfocytů fyziologie   MeSH
• antigeny nádorové metabolismus   MeSH
• buněčné linie MeSH
• CD4-pozitivní T-lymfocyty metabolismus   MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• NKT buňky metabolismus   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• RNA-helikasy metabolismus   MeSH
• spermatogeneze fyziologie   MeSH
• ubikvitin metabolismus   MeSH
• ubikvitinligasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• DCAF12 protein, human MeSH Prohlížeč
• IL17RB protein, human MeSH Prohlížeč
• Mov10 protein, human MeSH Prohlížeč
• proteasomový endopeptidasový komplex MeSH
• RNA-helikasy MeSH
• ubikvitin MeSH
• ubikvitinligasy MeSH