A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis

NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonadspecific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 36; pp. 22237 - 22248
Main Authors Yin, Yike, Cao, Shiyu, Fu, Huancheng, Fan, Xueying, Xiong, Jingfei, Huang, Qiuyue, Liu, Yu, Xie, Kun, Meng, Tie-Gang, Liu, Yuliang, Tang, Dan, Yang, Tingting, Dong, Biao, Qi, Shiqian, Nie, Ling, Xu, Wenming, Li, Fuping, Dai, Lunzhi, Sun, Qing-Yuan, Li, Zhonghan
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 08.09.2020
Subjects
Biological Sciences
Cell differentiation
Differentiation (biology)
Inflammasomes
Male sterility
Meiosis
Nuclear transport
Oligozoospermia
Proteasomes
Receptors
Recruitment
Reproductive failure
Spermatogenesis
Stem cell transplantation
Stem cells
Translocation
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Summary:NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonadspecific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro. Physiologically, knock out of Nlrp14 resulted in reproductive failure in both female and male mice. In adult male mice, Nlrp14 knockout (KO) inhibited differentiation of spermatogonial stem cells (SSCs) and meiosis, resulting in trapped SSCs in early stages, severe oligozoospermia, and sperm abnormality. Mechanistically, NLRP14 promoted spermatogenesis by recruiting a chaperone cofactor, BAG2, to bind with HSPA2 and form the NLRP14–HSPA2–BAG2 complex, which strongly inhibited ChIP-mediated HSPA2 polyubiquitination and promoted its nuclear translocation. Finally, loss of HSPA2 protection and BAG2 recruitment by NLRP14 was confirmed in a human nonsense germline variant associated with male sterility. Together, our data highlight a unique proteasome-mediated, noncanonical function of NLRP14 in PGCLC differentiation and spermatogenesis, providing mechanistic insights of gonad-specific NLRs in mammalian germline development.
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Edited by Vishva M. Dixit, Genentech, San Francisco, CA, and approved July 20, 2020 (received for review March 26, 2020)
Author contributions: Y.Y., H.Z., H.H., L.D., Q.-Y.S., and Z.L. designed research; Y.Y., S.C., H.F., X.F., J.X., Q.H., Yu Liu, K.X., T.-G.M, D.T., T.Y., and Z.L. performed research; H.F., Yuliang Liu, T.Y., L.N., W.X., F.L., and L.D. contributed new reagents/analytic tools; Y.Y., H.F., L.N., H.H., L.D., and Z.L. analyzed data; and Y.Y. and Z.L. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2005533117