Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor

Xiaoyang Liu,Jeffrey I Cohen,Susan Park Ochsner,Weizhong Li,Xiaoping Zhu,Senthilkumar Palaniyandi,C David Pauza,Jin Tang,Xiaoling Wu,Iowis Zhu

doi:10.1038/s41467-019-10865-y

Abstract

Human cytomegalovirus (HCMV) can persistently infect humans, but how HCMV avoids humoral immunity is not clear. The neonatal Fc receptor (FcRn) controls IgG transport from the mother to the fetus and prolongs IgG half-life. Here we show that US11 inhibits the assembly of FcRn with β2m and retains FcRn in the endoplasmic reticulum (ER), consequently blocking FcRn trafficking to the endosome. Furthermore, US11 recruits the ubiquitin enzymes Derlin-1, TMEM129 and UbE2J2 to engage FcRn, consequently initiating the dislocation of FcRn from the ER to the cytosol and facilitating its degradation. Importantly, US11 inhibits IgG-FcRn binding, resulting in a reduction of IgG transcytosis across intestinal or placental epithelial cells and IgG degradation in endothelial cells. Hence, these results identify the mechanism by which HCMV infection exploits an ER-associated degradation pathway through US11 to disable FcRn functions. These results have implications for vaccine development and immune surveillance.

Highlights

Human cytomegalovirus (HCMV) can persistently infect humans, but how HCMV avoids humoral immunity is not clear
Genes encoding HCMV proteins, US2, US3, US6, US10, US11, UL16, and UL18 were cloned by PCR amplification of viral DNA
The success of HCMV to infect a large proportion of the world’s population is due at least in part to its ability to evade the cellular immune system, and we have found that the virus inhibits antibody responses

Summary

Introduction

Human cytomegalovirus (HCMV) can persistently infect humans, but how HCMV avoids humoral immunity is not clear. US11 inhibits IgGFcRn binding, resulting in a reduction of IgG transcytosis across intestinal or placental epithelial cells and IgG degradation in endothelial cells. These results identify the mechanism by which HCMV infection exploits an ER-associated degradation pathway through US11 to disable FcRn functions. Viral infections are normally controlled through antibody-mediated and cellmediated immunity; the latter involves CD4+ and CD8+ T lymphocytes and natural killer (NK) cells. Anti-virus antibodies neutralize virions and stimulate immune cells expressing one or more FcγRs24. The HCMV genome encodes several decoy FcγRs, which may indirectly prevent the Fcγ-mediated effector consequences of anti-HCMV IgG antibodies[31,32,33]

Methods

Results

Conclusion