VIRAL IMMUNE EVASION OF FCRN FUNCTIONS

Abstract

Human Cytomegalovirus (HCMV) is known to evade host immunity, allowing it to persistently infect humans. Although the strategies of HCMV to evade cellular immunity is well studied, there is limited understanding on how HCMV antagonizes humoral immunity. The neonatal Fc receptor (FcRn), an MHC class I-related FcγR, plays a critical role in IgG-mediated humoral immunity. Through screening the HCMV proteome, we discovered that US11 specifically captured FcRn in both virally-infected and US11-expressing cells. US11 selectively inhibited the assembly of FcRn with β2m, impaired FcRn IgG binding capacity and blocked FcRn trafficking to the endosome by retention of FcRn in ER. Furthermore, US11 recruited Derlin-1 and E3 ubiquitin ligase TMEM129, to induce degradation of FcRn in US11+ or HCMV-infected cells. This complex led to the dislocation of FcRn from the ER to the cytosol and facilitated its degradation in an ubiquitination and proteasome-dependent manner. The cytosolic interaction between FcRn and Derlin-1 was shown necessary for degrading FcRn. FcRn is widely expressed in most cell susceptible to HCMV infection, including epithelial, endothelial and macrophage. Our data showed that either HCMV infection or recombinant US11 expression significantly inhibited human IgG transcytosis across polarized human primary intestinal epithelial Caco-2 cells, Vascular endothelial HMEC-1 cells and placental trophoblast BeWo cells, and facilitated considerable IgG degradation inside endothelial HMEC-1 cells. Hence, our results show that HCMV exploits the Derlin-1/TMEM129 pathway through US11 to disable FcRn, revealing a novel strategy for viral evasion from antibody mediated-immunity. We also studied whether HCMV viral FcγRs (gp34 and gp68) and US11 work together to facilitate IgG degradation. HCMV vFcγRs has been reported to internalize IgG via endocytosis. Interestingly, we found that in acidic pH (6.0) condition, the IgG binding capacity of gp34 was largely impaired while the IgG binding capacity of gp68 had minimal change. Consequently, in the presence of FcRn, gp34 did not enhance IgG degradation whereas gp68 significantly promoted the IgG degradation. Furthermore, the presence of US11 induced more gp34 and gp68-mediated IgG degradation in FcRn+ cells.