Abstract
Meiosis, which produces haploid progeny, is critical to ensuring both faithful genome transmission and genetic diversity. Proteasomes play critical roles at various stages of spermatogenesis, including meiosis, but the underlying mechanisms remain unclear. The atypical proteasomes, which contain the activator PA200, catalyze the acetylation-dependent degradation of the core histones in elongated spermatids and DNA repair in somatic cells. We show here that the testis-specific proteasome subunit α4s/PSMA8 is essential for male fertility by promoting proper formation of spermatoproteasomes, which harbor both PA200 and constitutive catalytic subunits. Immunostaining of a spermatocyte marker, SYCP3, indicated that meiosis was halted at the stage of spermatocytes in the α4s-deficient testes. α4s stimulated the in vitro degradation of the acetylated core histones, instead of nonacetylated histones, by the PA200-proteasome. Deletion of α4s blocked degradation of the core histones at DNA damage loci in spermatocytes, leading to meiotic arrest at metaphase I. Thus, α4s is required for histone degradation at meiotic DNA damage loci, proper progression of meiosis, and fertility in males by promoting proper formation of spermatoproteasomes. These results are important for understanding male infertility and might provide potential targets for male contraception or treatment of male infertility.
Highlights
Proteasomes are responsible for degradation of most cellular proteins, and their inhibitors, such as bortezomib and carfilzomib, are clinically used to treat multiple myeloma and mantle cell lymphoma [1]
We demonstrate here that α4s/PSMA8 is required for the removal of the core histones at DNA damage loci, the proper progression of meiosis, and fertility in males by promoting formation of the properly assembled spermatoproteasome, which harbors both PA200 and regular constitutive catalytic subunits
Immunostaining of SYCP3 indicated that meiosis, which is not yet completed at postnatal day 20, was halted at the stage of spermatocytes in the α4s-deficient testes (Fig. 1, E–F)
Summary
Received for publication, October 20, 2020, and in revised form, November 18, 2020 Published, Papers in Press, December 1, 2020, https://doi.org/10.1074/jbc.RA120.016485 Zi-Hui Zhang1, Tian-Xia Jiang1,*, Lian-Bin Chen1, Wenhui Zhou2, Yixun Liu3, Fei Gao3 , and Xiao-Bo Qiu1,* From the 1Key Laboratory of Cell Proliferation & Regulation Biology, Ministry of Education and College of Life Sciences, Beijing Normal University, Beijing, China; 2Medical Center for Human Reproduction, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; and 3State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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