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

作者：Yike Yin, Shiyu Cao, Huancheng Fu, Xueying Fan, Jingfei Xiong, Qiuyue Huang, Yu Liu, Kun Xie, Tie‐Gang Meng, Yuliang Liu, Dan Tang, Tingting Yang, Biao Dong, Shiqian Qi, Ling Nie, Huiyuan Zhang, Hongbo Hu, Wenming Xu, Fuping Li, Lunzhi Dai, Qing‐Yuan Sun, Zhonghan Li · 发表于：Proceedings of the National Academy of Sciences · 年份：2020 · DOI：10.1073/pnas.2005533117 · 被引用次数：49 · 研究领域：Sperm and Testicular Function、Reproductive System and Pregnancy、Reproductive Biology and Fertility

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 gonad-specific 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.