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J Exp Med. Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection
[Source: The Journal of Experimental Medicine, full page: (LINK). Abstract, edited.]
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Published July 1, 2013 - The Rockefeller University Press, doi: 10.1084/jem.20121806 - ? 2013 Wang et al.
Article
Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection
Xiu-Xing Wang 1, Pu Ying 1, Fan Diao 1, Qiang Wang 1, Dan Ye 1, Chen Jiang 1, Ning Shen 1, Na Xu 1, Wei-Bo Chen 1, Shan-Shan Lai 1, Shan Jiang 1, Xiao-Li Miao 2, Jin Feng 2, Wei-Wei Tao 1, Ning-Wei Zhao 5, Bing Yao 1, Zhi-Peng Xu 1, Hai-Xiang Sun 1, Jian-Min Li 3, Jia-Hao Sha 3, Xing-Xu Huang 1, Bin Xue 1, Hong Tang 4, Xiang Gao 1, and Chao-Jun Li 1
Author Affiliations: <SUP>1</SUP>MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and Jiangsu Key Laboratory of Molecular Medicine of the School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210061, China <SUP>2</SUP>Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China <SUP>3</SUP>State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China <SUP>4</SUP>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China <SUP>5</SUP>Department of Life Science and Clinical Medicine, Shimadzu (China) Co., Ltd., Shanghai 200052, China
CORRESPONDENCE: Xiang Gao: gaoxiang@nju.edu.cn OR Chao-Jun Li: licj@nju.edu.cn
Abstract
Mumps commonly affects children 5?9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell?only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients? fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-κB signaling pathways were constitutively activated in GGPPS<SUP>−/−</SUP> Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS<SUP>−/−</SUP> Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.
Submitted: 10 August 2012 Accepted: 6 June 2013
This article is distributed under the terms of an Attribution?Noncommercial?Share Alike?No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution?Noncommercial?Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
-Article
Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection
Xiu-Xing Wang 1, Pu Ying 1, Fan Diao 1, Qiang Wang 1, Dan Ye 1, Chen Jiang 1, Ning Shen 1, Na Xu 1, Wei-Bo Chen 1, Shan-Shan Lai 1, Shan Jiang 1, Xiao-Li Miao 2, Jin Feng 2, Wei-Wei Tao 1, Ning-Wei Zhao 5, Bing Yao 1, Zhi-Peng Xu 1, Hai-Xiang Sun 1, Jian-Min Li 3, Jia-Hao Sha 3, Xing-Xu Huang 1, Bin Xue 1, Hong Tang 4, Xiang Gao 1, and Chao-Jun Li 1
Author Affiliations: <SUP>1</SUP>MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and Jiangsu Key Laboratory of Molecular Medicine of the School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210061, China <SUP>2</SUP>Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China <SUP>3</SUP>State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China <SUP>4</SUP>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China <SUP>5</SUP>Department of Life Science and Clinical Medicine, Shimadzu (China) Co., Ltd., Shanghai 200052, China
CORRESPONDENCE: Xiang Gao: gaoxiang@nju.edu.cn OR Chao-Jun Li: licj@nju.edu.cn
Abstract
Mumps commonly affects children 5?9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell?only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients? fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-κB signaling pathways were constitutively activated in GGPPS<SUP>−/−</SUP> Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS<SUP>−/−</SUP> Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.
Submitted: 10 August 2012 Accepted: 6 June 2013
This article is distributed under the terms of an Attribution?Noncommercial?Share Alike?No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution?Noncommercial?Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
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