Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection.
Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection.
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支持细胞中蛋白质异戊二烯化的改变与儿童腮腺炎感染引起的成人不孕有关
DOI：
10.1084/jem.20121806
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发表时间：
2013-07-29
期刊：
影响因子：
--
通讯作者：
Li CJ
中科院分区：
文献类型：
--
作者：
Wang XX;Ying P;Diao F;Wang Q;Ye D;Jiang C;Shen N;Xu N;Chen WB;Lai SS;Jiang S;Miao XL;Feng J;Tao WW;Zhao NW;Yao B;Xu ZP;Sun HX;Li JM;Sha JH;Huang XX;Shi QH;Tang H;Gao X;Li CJ
儿童流行性腮腺炎感染或缺失导致GGPPS的缺失导致MAPK和NF-kB信号的结构性激活，从而诱导精原细胞凋亡、巨噬细胞侵入生精小管和不育。流行性腮腺炎通常影响5-9岁的儿童，在某些情况下可能导致永久性成人不育。然而，这种长期影响的病因仍不清楚。腮腺炎感染会导致生精上皮的进行性退化，偶尔还会出现仅支持细胞综合征。因此，残留的Sertoli细胞可能对炎愈合后精子发生的恢复至关重要。在这里，我们报告了蛋白质法尼化/香叶化平衡对患者的生育能力至关重要。在有腮腺炎感染病史的不育症患者中，香叶基香叶基二磷酸合成酶1(GGPPS)的表达因启动子甲基化升高而降低。当我们在小鼠Sertoli细胞中删除GGPPS时，这些细胞保持完好，而相邻的精原细胞在出生后第5天后显著减少。由于H-κ的法尼化增强，促炎症的MAPK和NF-RAS B信号通路在−/−支持细胞中被结构性地激活。−/−支持细胞分泌一系列细胞因子刺激精原细胞凋亡，并分泌趋化因子诱导巨噬细胞侵入生精小管。入侵的巨噬细胞进一步阻碍了精原细胞的发育，导致了直到成年的长期影响。值得注意的是，在EMCV挑战的小鼠中，这种缺陷可以通过给予GGPP来修复。我们的结果提示了一种新的机制，通过这种机制，儿童时期的腮腺炎感染会导致成人不育。
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.
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影响因子：
5.3
作者：
Mikovits, JA;Young, HA;Ruscetti, FW
通讯作者：
Ruscetti, FW
影响因子：
1.5
作者：
Lécureuil, C;Fontaine, I;Guillou, F
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Guillou, F
影响因子：
6.6
作者：
Casella, R;Leibundgut, B;Gasser, TC
通讯作者：
Gasser, TC
DOI：
10.1073/pnas.0407639101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Andrejeva, J;Childs, KS;Randall, RE
通讯作者：
Randall, RE
影响因子：
3.6
作者：
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通讯作者：
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