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Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection

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      Abstract

      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.

      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 −/− 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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      Monocyte and macrophage heterogeneity.

      Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
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        The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.

        Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses. In this report, we identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling, as assessed by functional screening and assays. A helicase domain with intact ATPase activity was responsible for the dsRNA-mediated signaling. The caspase recruitment domain transmitted 'downstream' signals, resulting in the activation of transcription factors NF-kappaB and IRF-3. Subsequent gene activation by these factors induced antiviral functions, including type I interferon production. Thus, RIG-I is key in the detection and subsequent eradication of the replicating viral genomes.
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          Chemokines--chemotactic cytokines that mediate inflammation.

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            Author and article information

            Affiliations
            [1 ]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
            [2 ]Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
            [3 ]State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China
            [4 ]Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
            [5 ]Department of Life Science and Clinical Medicine, Shimadzu (China) Co., Ltd., Shanghai 200052, China
            Author notes
            CORRESPONDENCE Xiang Gao: gaoxiang@ 123456nju.edu.cn OR Chao-Jun Li: licj@ 123456nju.edu.cn
            Journal
            J Exp Med
            J. Exp. Med
            jem
            The Journal of Experimental Medicine
            The Rockefeller University Press
            0022-1007
            1540-9538
            29 July 2013
            : 210
            : 8
            : 1559-1574
            23825187 3727317 20121806 10.1084/jem.20121806
            © 2013 Wang et al.

            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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