The Protein Prenylation Alteration In Sertoli Cells Is Associated With Adult Infertility Resulted From Childhood Mumps Infection

Mumps commonly affects children aged5-9years and results in permanent adult sterility in rare cases. However, the etiology of this long-term effect remains unclear. Mumps orchitis results in macrophage proliferation and progressive degeneration of seminiferous epithelium which can lead to infertility. Thus, understanding of the mechanism underlying immune response in the testis before puberty is matters of clinical importance to prevent children from future adulthood infertility. Sometimes, Mumps can leads to Sertoli cell-only syndrome. Sertoli cells stand at the centre of the regulation of immune privilege during adulthood. Thus the left Sertoli cell after Mumps infection may play an important role in the recovery of spermatogenesis after mumps orchitis healing.FPP and GGPP are used for the prenylation modification of the proteins with CaaX motif in their carbon terminals, like RAS superfamily of GTPases. Then the RAS activate the MAPK signaling pathway. Previous reports indicate that a mevalonate metabolic pathway inhibitor, statin has been used as an anti-inflammatory drug by inhibiting both farnesylation and geranylgeranylation of protein. It has been reported that the protein prenylation level and the ratio of geranylgeranylated (modified with GGPP moiety) to farnesylated (modified with FPP moiety) protein were higher in the premeiotic and meiotic stages of spermatogenesis before sexual maturity and decreased with age in rat. This indicates that the protein prenylation may have important role in testis’s immune regulation.In the present here, we bred testicular Sertoli cell specific GGPPS knockout mice with the goal to define whether and how protein prenylation can affect Sertoli cell mediated inflammation response. We find:1. The alteration of protein prenylation by GGPPS deletion in Sertoli cells during childhood leads to adult infertility because of spermatogonia but not Sertoli cell defect as earlier as5th postnatal day.2. Inactivation of GGPPS in Sertoli cells results in cytokines and chemokines release, which induces spermatogonium apoptosis and seminiferous tubule macrophage invasion.3. MAPK Erk1/2and NF-B are constitutively activated by GGPPS deletion in Sertoli cells, which is responsible for the spermatogonial cell loss and testis defects.4. GGPPS deletion results in an increase of H-Ras farnesylation in Sertoli cells that responsible for spontaneous hyper-inflammatory response in the testes.5. EMCV challenge results in mouse testis defect through protein prenylation alteration by inhibiting GGPPS expression.Our results show that GGPPS regulated protein prenylation is crucial for spermatogonia survival during childhood when there is no BTB and gonadotrophin. Inactivating GGPPS in testicular Sertoli cell resulted in sustained activation of H-RAS proteins and spontaneous hyper-inflammation response in the early stage of testis development. Our results indicated that the protein prenylation in Sertoli cell was critical to regulate orchitis before puberty.Our results suggest a novel mechanism by which mumps infection during human childhood results in adult infertility.