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 , Qing-Hua Shi 4 , Hong Tang 2 , Xiang Gao , 1 , Chao-Jun Li , 1
29 July 2013
Loss of GGPPS from childhood mumps infection or deletion in mice results in constitutively activated MAPK and NF-kB signaling that induces spermatogonium apoptosis, macrophage invasion into seminiferous tubules, and sterility.
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 −/− Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS −/− 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.