CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

0544148 - ÚMG 2022 RIV CH eng J - Journal Article
Liďák, Tomáš - Baloghová, Nikol - Kořínek, Vladimír - Sedláček, Radislav - Balounová, Jana - Kašpárek, Petr - Čermák, Lukáš
CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation.
International Journal of Molecular Sciences. Roč. 22, č. 10 (2021), č. článku 5394. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GA18-27408S; GA MŠMT(CZ) LM2018126; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT(CZ) LQ1604
Institutional support: RVO:68378050
Keywords : dcaf12 * wdr40a * mov10 * C-terminal degron * spermatogenesis * T cell activation
OECD category: Biochemistry and molecular biology
Impact factor: 6.208, year: 2021
Method of publishing: Open access
https://www.mdpi.com/1422-0067/22/10/5394

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 gamma-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.
Permanent Link: http://hdl.handle.net/11104/0321191