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

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Significance

NOD-like receptors (NLRs) are traditionally recognized as key surveillance pattern recognition receptors (PRRs) during innate immune regulation. Several NLRs exhibit highly restricted expression in mammalian germline, where their physiological functions are largely unknown. Here we report that Nlrp14, an NLR specifically expressed in testis and ovary, plays a critical role in regulating germ cell differentiation and reproduction. Nlrp14 deficiency led to decreased primordial germ cell-like cell (PGCLC) differentiation in vitro and reproduction failure in both male and female mice in vivo. In the male mice, Nlrp14 knockout strongly compromised differentiation of spermatogonial stem cells and meiosis. Mechanistically, NLRP14 protected HSPA2 from proteasome-mediated degradation by recruiting BAG2, loss of which was further confirmed in a human mutation associated with male sterility.

Abstract

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.

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Most cited references 47

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Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells.

Katsuhiko Hayashi, Hiroshi Ohta, Kazuki Kurimoto … (2011)

The generation of properly functioning gametes in vitro requires reconstitution of the multistepped pathway of germ cell development. We demonstrate here the generation of primordial germ cell-like cells (PGCLCs) in mice with robust capacity for spermatogenesis. PGCLCs were generated from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) through epiblast-like cells (EpiLCs), a cellular state highly similar to pregastrulating epiblasts but distinct from epiblast stem cells (EpiSCs). Reflecting epiblast development, EpiLC induction from ESCs/iPSCs is a progressive process, and EpiLCs highly competent for the PGC fate are a transient entity. The global transcription profiles, epigenetic reprogramming, and cellular dynamics during PGCLC induction from EpiLCs meticulously capture those associated with PGC specification from the epiblasts. Furthermore, we identify Integrin-β3 and SSEA1 as markers that allow the isolation of PGCLCs with spermatogenic capacity from tumorigenic undifferentiated cells. Our findings provide a paradigm for the first step of in vitro gametogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

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The NLRP3 inflammasome: a sensor for metabolic danger?

Kate Schroder, Rongbin Zhou, Jurg Tschopp (2010)

Interleukin-1beta (IL-1beta), reactive oxygen species (ROS), and thioredoxin-interacting protein (TXNIP) are all implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). Here we review mechanisms directing IL-1beta production and its pathogenic role in islet dysfunction during chronic hyperglycemia. In doing so, we integrate previously disparate disease-driving mechanisms for IL-1beta, ROS, and TXNIP in T2DM into one unifying model in which the NLRP3 inflammasome plays a central role. The NLRP3 inflammasome also drives IL-1beta maturation and secretion in another disease of metabolic dysregulation, gout. Thus, we propose that the NLRP3 inflammasome contributes to the pathogenesis of T2DM and gout by functioning as a sensor for metabolic stress.

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The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.

Teresa Thurston, Grigory Ryzhakov, Stuart Bloor … (2009)

Cell-autonomous innate immune responses against bacteria attempting to colonize the cytosol of mammalian cells are incompletely understood. Polyubiquitylated proteins can accumulate on the surface of such bacteria, and bacterial growth is restricted by Tank-binding kinase (TBK1). Here we show that NDP52, not previously known to contribute to innate immunity, recognizes ubiquitin-coated Salmonella enterica in human cells and, by binding the adaptor proteins Nap1 and Sintbad, recruits TBK1. Knockdown of NDP52 and TBK1 facilitated bacterial proliferation and increased the number of cells containing ubiquitin-coated salmonella. NDP52 also recruited LC3, an autophagosomal marker, and knockdown of NDP52 impaired autophagy of salmonella. We conclude that human cells utilize the ubiquitin system and NDP52 to activate autophagy against bacteria attempting to colonize their cytosol.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 8 September 2020

Publication date (Electronic): 24 August 2020

Publication date PMC-release: 24 August 2020

Volume: 117

Issue: 36

Pages: 22237-22248

Affiliations

[1] ^aCenter for Growth Metabolism & Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University , 610064 Chengdu, China;

[2] ^bDepartment of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy , 610064 Chengdu, China;

[6] ^cState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , 100101 Beijing, China;

[7] ^dFertility Preservation Lab, Reproductive Medicine Center, Guangdong Second Provincial General Hospital , 510317 Guangzhou, China;

[8] ^eSichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Giant Panda Breeding Research Base , 610081 Chengdu, China;

[4] ^fDepartment of Urology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy , 610064 Chengdu, China;

[9] ^gHuman Sperm Bank, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital of Sichuan University , 610064 Chengdu, China;

[5] ^hDepartment of Pathology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy , 610064 Chengdu, China;

[3] ⁱDepartment of Rheumatology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy , 610064 Chengdu, China;

[10] ^jDepartment of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University , 610064 Chengdu, China;

[11] ^kUniversity of Chinese Academy of Sciences , 100000 Beijing, China;

[12] ^lNational Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University , 610064 Chengdu, China

Author notes

¹To whom correspondence may be addressed. Email: zhonghan.li@ 123456scu.edu.cn .

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.