Proteasome subunit α4s is essential for formation of spermatoproteasomes and histone degradation during meiotic DNA repair in spermatocytes

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. 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. 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 (1Richardson P.G. Xie W. Mitsiades C. Chanan-Khan A.A. Lonial S. Hassoun H. Avigan D.E. Oaklander A.L. Kuter D.J. Wen P.Y. Kesari S. Briemberg H.R. Schlossman R.L. Munshi N.C. Heffner L.T. et al.Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.J. Clin. Oncol. 2009; 27: 3518-3525Crossref PubMed Scopus (215) Google Scholar). Proteasomes usually contain one 20S catalytic core particle (CP) and one or two regulatory particles, which serve as activators, including the 19S regulatory particle, PA28α/β, PA28γ, and PA200 (2Stadtmueller B.M. Hill C.P. Proteasome activators.Mol. Cell. 2011; 41: 8-19Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). The typical 26S proteasome contains the 19S regulatory particle and the 20S CP with constitutive catalytic subunits (including β1, β2, and β5) and promotes degradation of the ubiquitinated proteins. The immunoproteasome contains the 20S CP with the variants of catalytic subunits (including β1i, β2i, and β5i) (3Jiang T.X. Zhao M. Qiu X.B. Substrate receptors of proteasomes.Biol. Rev. Camb. Philos. Soc. 2018; 93: 1765-1777Crossref PubMed Scopus (11) Google Scholar). Certain fraction of 20S CPs in the PA200-containing proteasomes in testes harbors the catalytic subunits of the immunoproteasome, rather than regular catalytic subunits (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The PA200-containing proteasomes promote the acetylation-dependent degradation of the core histones during somatic DNA repair and spermiogenesis (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 5Mandemaker I.K. Geijer M.E. Kik I. Bezstarosti K. Rijkers E. Raams A. Janssens R.C. Lans H. Hoeijmakers J.H. Demmers J.A. Vermeulen W. Marteijn J.A. DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones.EMBO Rep. 2018; 19e45566Crossref PubMed Scopus (22) Google Scholar). In testes, proteasomes are largely specialized into spermatoproteasomes, which contain the testis-specific 20S subunit α4s/PSMA8 and/or the catalytic subunits of the immunoproteasome in addition to PA200 (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). α4s is specifically expressed in pachytene spermatocytes and the cells derived from them, including spermatids and spermatozoa (6Uechi H. Hamazaki J. Murata S. Characterization of the testis-specific proteasome subunit alpha4s in mammals.J. Biol. Chem. 2014; 289: 12365-12374Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Meiosis includes 2 cell divisions to produce haploid progeny. Spermatogenesis is a complex process in which primary spermatocytes progress through leptotene, zygotene, pachytene, and diplotene stages at prophase I of meiosis. After completion of meiosis I, secondary spermatocytes rapidly go through meiosis II to form haploid spermatids, which undergo spermiogenesis to differentiate into spermatozoa (7Yin Y. Lin C. Kim S.T. Roig I. Chen H. Liu L. Veith G.M. Jin R.U. Keeney S. Jasin M. Moley K. Zhou P. Ma L. The E3 ubiquitin ligase cullin 4A regulates meiotic progression in mouse spermatogenesis.Dev. Biol. 2011; 356: 51-62Crossref PubMed Scopus (57) Google Scholar, 8Bao J. Bedford M.T. Epigenetic regulation of the histone-to-protamine transition during spermiogenesis.Reproduction. 2016; 151: R55-R70Crossref PubMed Scopus (93) Google Scholar, 9Barral S. Morozumi Y. Tanaka H. Montellier E. Govin J. de Dieuleveult M. Y. S. P. et transition in male Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). meiosis I, undergo genetic by which DNA are and to of the genetic The repair of DNA is critical to meiosis and to meiotic 2011; 27: Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. J. Kim S. Zhu Jasin M. Keeney S. The of mouse meiotic and 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). The and in a the to the DNA damage Thus, male are with DNA damage response proteins, including form of the histone at the the of Biol. Google Scholar). The at a than typical J. S. J. Kim S. Zhu Jasin M. Keeney S. The of mouse meiotic and 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, L. M. Keeney S. Jasin M. of the for male 2011; PubMed Scopus Google Scholar). through a the of Biol. Google Scholar). We here that α4s/PSMA8 is required for the of the core histones at DNA damage loci, the proper progression of meiosis, and fertility in males by promoting formation of the which harbors both PA200 and regular constitutive catalytic subunits. the of two the of α4s/PSMA8 in male meiosis L. The subunit of the is essential for proper meiotic and mouse PubMed Scopus Google Scholar, Ji K. J. Meiosis I progression in a of testis-specific 20S core PubMed Scopus Google Scholar). that the of α4s/PSMA8 to male infertility in the underlying mechanisms provide are that proteasomes are the targets (1Richardson P.G. Xie W. Mitsiades C. Chanan-Khan A.A. Lonial S. Hassoun H. Avigan D.E. Oaklander A.L. Kuter D.J. Wen P.Y. Kesari S. Briemberg H.R. Schlossman R.L. Munshi N.C. Heffner L.T. et al.Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.J. Clin. Oncol. 2009; 27: 3518-3525Crossref PubMed Scopus (215) Google results might provide potential targets for male contraception or treatment of male infertility. the of α4s in spermatogenesis, the with of α4s and of α4s to the and of testes in and male infertility but fertility or male and spermatids or spermatozoa in the and the from the α4s-deficient a fraction of haploid of cells was in the α4s-deficient testes that a of spermatids meiosis. complex and are in spermatocytes R.L. A. M. C. for of meiotic prophase J. PubMed Scopus Google Scholar, A. complex and PubMed Google Scholar). Immunostaining of indicated that meiosis, which is at was halted at the stage of spermatocytes in the α4s-deficient testes specifically by S. Zhang C. The is required for and of in the S. A. PubMed Scopus Google the formation of cells in testes was by α4s The typical 26S proteasome contains constitutive catalytic subunits β1, β2, and β5) in addition to the 19S regulatory particle, the immunoproteasome contains catalytic subunits β1i, β2i, and β5i) (2Stadtmueller B.M. Hill C.P. Proteasome activators.Mol. Cell. 2011; 41: 8-19Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). Deletion of α4s the of PA200 and constitutive catalytic subunits β1, β2, and β5) but the of the catalytic subunits of the immunoproteasome and β5i) and the proteasome and in testes The of and the subunits from the typical 26S proteasome and in the α4s-deficient testes the mechanisms for of α4s the of various proteasome that the to their that α4s in various proteasome subunits at by their or the in cell spermatocytes, which contain of at stages DNA replication and in the process of meiosis I, and haploid of of cells was as indicated by the of and and which spermatids and spermatocytes, R.L. A. M. C. for of meiotic prophase J. PubMed Scopus Google Scholar, The of Biol. PubMed Scopus Google Scholar). α4s the of the proteasome subunits in spermatocytes in with in and and that in the of subunits to in the proteasomal at or and a in the of PA200 was of constitutive catalytic subunits with immunoproteasome was at in the α4s-deficient testes, as by the in the of and for proteasomes and that of α4s of proteasomes in testes but in testes from at with the typical 26S and with the immunoproteasome and Thus, α4s is required for the formation of the which contains both PA200 and regular catalytic in of α4s the of PA200 and regular catalytic subunits in proteasomes of testes. and of the from the testes of the and the α4s-deficient was by the with in the or of which the 20S of the of of the from the testes of the and the α4s-deficient as a the proteasomal of of the and the α4s-deficient are of one with at two The usually cells by the to the of in the the show the or for cells. Deletion of α4s the of the spermatocytes in the of testes provide of the of C. H. Y. Liu for 2009; PubMed Scopus Google Scholar). Deletion of α4s the of the spermatocytes in the of testes to that in the testes, the for the of spermatocytes was than that for or cells during mouse and are in and Deletion of α4s formation of or which by and In pachytene spermatocytes, is as In to diplotene spermatocytes, is to the of the DNA damage response in mouse roles for of the complex in meiotic 2013; PubMed Scopus Google Scholar). of α4s the of the cells in testes and the of at various stages of prophase I of meiosis in spermatocyte in the is leading to meiotic in the and are from histone A. Zhang Huang H. S. S. A.L. Montellier E. J. S. A. et histone and are of Cell. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). are required for meiotic with a in are in is required for and the prophase arrest of PubMed Scopus Google Scholar, M. S. M. de Jasin M. Keeney S. of in mouse spermatocytes at Cell. Biol. PubMed Scopus Google Scholar). male meiotic arrest with A. K. P. A. is required for and of in male mouse Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The and the are usually during the in the testes S. H. S. K. of pachytene in meiotic PubMed Scopus Google but in the α4s-deficient testes. are usually during but in the α4s-deficient testes Thus, of α4s essential of α4s in meiotic DNA and repair of DNA are critical to meiosis and genetic and to meiotic 2011; 27: Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. J. Kim S. Zhu Jasin M. Keeney S. The of mouse meiotic and 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). a DNA repair important in the formation of meiotic in C. A. of mouse in DNA repair and meiotic PubMed Scopus Google Scholar). Deletion of α4s in the of the of in the of the α4s-deficient spermatocytes and is required for formation in meiotic DNA repair and the from These are in and in The mouse is required for meiotic Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, de E. M. M. L. Liu A.A. C. A. in complex meiotic and PubMed Scopus Google Scholar). In the α4s-deficient spermatocytes, the for was to that in the prophase I and that of α4s the of during prophase I. the of α4s in meiotic DNA the to in the of cells a with as meiotic DNA by 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in the the and the α4s-deficient spermatocytes at prophase I In with in the testes, the of and but the of the acetylated histones, including the of the core histones as and in the of the α4s-deficient testes The of acetylated histones in the α4s-deficient testes to the of spermatids, of the core histones is to with histone or degradation during the of spermatids (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, Lin acetylated is with histone in PubMed Scopus Google Scholar). the of the cell spermatocytes and haploid of α4s the of in the of spermatocytes in addition to the of and and DNA repair is the of DNA repair the of spermatocyte in the α4s-deficient testes the of and in both the of α4s-deficient testes and the of spermatocytes and that of α4s might the repair of DNA in of meiosis and the by of of α4s the of spermatocytes at metaphase I and the such as I and I with DNA J. the of the 2009; PubMed Scopus Google Scholar). was and DNA at metaphase I in the testes, with DNA in spermatocytes at metaphase I in the α4s-deficient testes In of α4s the of DNA by at metaphase I of spermatocytes These results that of α4s the repair of at metaphase I in with meiotic are to in both and that histones might during meiotic repair M. by PubMed Scopus Google Scholar, K. K. of a to in the mouse and PubMed Scopus Google Scholar). that in the testes, with as by and in the α4s-deficient testes that degradation of the acetylated histones was at loci in the α4s-deficient testes. that the PA200-containing proteasomes the acetylated core histones during somatic DNA repair and spermiogenesis (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). the of α4s in histone the acetylated core histones with the 20S catalytic from testes, which contain in the or of The 20S particle from which contain as a α4s stimulated the in vitro degradation of the acetylated core histones, instead of nonacetylated histones by the of α4s the degradation of the acetylated core histones in from results that α4s degradation of the core histones during meiotic DNA and is required for proper progression of meiosis and fertility in male The repair of DNA is critical to the completion of meiosis and to meiotic 2011; 27: Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. J. Kim S. Zhu Jasin M. Keeney S. The of mouse meiotic and 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). In in meiotic DNA repair usually to arrest at meiotic prophase I de P. of in and PubMed Scopus Google and M. S. M. de Jasin M. Keeney S. of in mouse spermatocytes at Cell. Biol. PubMed Scopus Google Scholar). meiotic DNA repair is including remain I in M.T. A. A. J.A. J. and of in the of PubMed Scopus Google Scholar). PA200 promotes the acetylation-dependent degradation of the core histones during somatic DNA repair and in elongated spermatids (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). that the is required for the histone degradation with DNA damage A. A. M. J. degradation in response to DNA damage and Biol. PubMed Scopus Google Scholar). that α4s is required for the of acetylated core histones during meiotic DNA repair in spermatocytes and male In of PA200 the male fertility by the degradation of the core histone during the of spermatids meiosis (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). of histones by catalytic subunits in the 20S We previously that contain α4s/PSMA8 and/or the catalytic subunits of in addition to PA200, the or contain both α4s and the catalytic subunits of the immunoproteasome (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). In show that α4s is required for the formation of the which contains both PA200 and constitutive catalytic subunits β1, β2, and in testes. catalytic subunits of the immunoproteasome β1i, β2i, and β5i) at the constitutive catalytic subunits in the testes. We provide that α4s the in the in various proteasome subunits at by their or a the of α4s was than that of PA200 The constitutive proteasome subunits and immunoproteasome subunits might for the in the Thus, α4s a than PA200 in histone degradation during The α4s and is the of the subunits (6Uechi H. Hamazaki J. Murata S. Characterization of the testis-specific proteasome subunit alpha4s in mammals.J. Biol. Chem. 2014; 289: 12365-12374Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). of the by the of and α4s are is that the for and for α4s (6Uechi H. Hamazaki J. Murata S. Characterization of the testis-specific proteasome subunit alpha4s in mammals.J. Biol. Chem. 2014; 289: 12365-12374Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). The PA200 and the 20S catalytic particle in Characterization of 20S and proteasome Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In the of to of the 20S particle are and from the proteasome into at the of the PA200 but the are and for the for and Characterization of 20S and proteasome Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The in α4s might a than for the of the 20S particle with PA200, and for the of regular catalytic including β1, β2, and in to their immunoproteasome the of two the of α4s/PSMA8 in male meiosis L. The subunit of the is essential for proper meiotic and mouse PubMed Scopus Google Scholar, Ji K. J. Meiosis I progression in a of testis-specific 20S core PubMed Scopus Google Scholar). Zhang et Ji K. J. Meiosis I progression in a of testis-specific 20S core PubMed Scopus Google that the of DNA damage repair and in testes by the of α4s/PSMA8 as by et L. The subunit of the is essential for proper meiotic and mouse PubMed Scopus Google in the of DNA damage repair and the and the spermatocytes as by In to the of the cell the of DNA damage in the spermatocytes by and results by of results that the of DNA damage repair and in the spermatocytes, which in with by et in the the of DNA damage repair in the spermatocytes, that of α4s to of DNA as by and at metaphase I, that α4s is essential for meiotic DNA repair and the proper progression of meiosis. two that the of α4s/PSMA8 to male infertility in the underlying mechanisms in their are from L. The subunit of the is essential for proper meiotic and mouse PubMed Scopus Google Scholar, Ji K. J. 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The of which the of and/or results in spermatocyte during the pachytene stage meiotic and to in Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). that in in such as and meiotic arrest A. K. P. A. is required for and of in male mouse Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, P. meiotic repair and of during in PubMed Scopus Google Scholar). Thus, the results from are important for understanding male infertility and might provide a for the treatment of male infertility. in to and with and by is a of targets for P. Ma L. M.E. S. Yu J. S. of for male Full Text Full Text PDF PubMed Scopus Google Scholar, and stress in the Biol. PubMed Google Scholar, J. Montellier E. S. S. P. S. A. A.L. P. K. A. H. et male genome by J. 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Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, C. M. and of proteasome activator PubMed Scopus Google Scholar). the from the testes was with The was with the of of of of of and 2 of and was with of the but a to The with PA200 with of the of of of of of of and and to The was with of the with of of in the and the was to the The with PA200 from the a with of the of and with a of to in the The PA200 from the was by for a to from or cells to (4Qian M.X. Pang Y. Liu C.H. Haratake K. Du B.Y. Ji D.Y. Wang G.F. Zhu Q.Q. Song W. Yu Y. Zhang X.X. Huang H.T. Miao S. Chen L.B. Zhang Z.H. et al.Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.Cell. 2013; 153: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (178) Google histones from acetylated by in the of of of and of and the was by The degradation of acetylated histones was in the of of of and of at and a was with of the 20S proteasome and of acetylated histones in the or of of for two by and and of the and and by The that the of are from the and for to We in The that of with the of the with the of J. and W. α4s-deficient cells into and with the of L. Y. L. and and the which was by and the and was by the of of and of the of of and the of of and of

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