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

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

doi:10.1038/s41467-019-10865-y

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

Nat Commun. 2019 Jul 9;10(1):3020. doi: 10.1038/s41467-019-10865-y.

Authors

Xiaoyang Liu¹, Senthilkumar Palaniyandi¹, Iowis Zhu¹, Jin Tang¹, Weizhong Li¹, Xiaoling Wu¹, Susan Park Ochsner¹, C David Pauza^{2

3}, Jeffrey I Cohen⁴, Xiaoping Zhu^{5

6}

Affiliations

¹ Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, 20742, USA.
² Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
³ American Gene Technologies, Rockville, MD, 20850, USA.
⁴ Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20814, USA.
⁵ Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, 20742, USA. [email protected].
⁶ Maryland Pathogen Research Institute, University of Maryland, College Park, MD, 20742, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Cytomegalovirus / immunology*
Cytomegalovirus / pathogenicity
Cytomegalovirus Infections / immunology*
Cytomegalovirus Infections / virology
Endoplasmic Reticulum-Associated Degradation / immunology
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class I / metabolism*
Humans
Immune Evasion*
Immunity, Humoral*
Immunoglobulin G / immunology
Immunoglobulin G / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mutagenesis, Site-Directed
RNA, Small Interfering / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / immunology
RNA-Binding Proteins / metabolism*
Receptors, Fc / immunology
Receptors, Fc / metabolism*
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Viral Proteins / genetics
Viral Proteins / immunology
Viral Proteins / metabolism*

Substances

DERL1 protein, human
Histocompatibility Antigens Class I
Immunoglobulin G
Membrane Proteins
RNA, Small Interfering
RNA-Binding Proteins
Receptors, Fc
US11 protein, herpesvirus
Viral Proteins
UBE2J2 protein, human
Ubiquitin-Conjugating Enzymes
TMEM129 protein, human
Ubiquitin-Protein Ligases
Fc receptor, neonatal

Abstract

Publication types

MeSH terms

Substances

Grants and funding