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 and Xiaoping Zhu ()
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Xiaoyang Liu: University of Maryland
Senthilkumar Palaniyandi: University of Maryland
Iowis Zhu: University of Maryland
Jin Tang: University of Maryland
Weizhong Li: University of Maryland
Xiaoling Wu: University of Maryland
Susan Park Ochsner: University of Maryland
C. David Pauza: University of Maryland School of Medicine
Jeffrey I. Cohen: National Institute of Allergy and Infectious Diseases, NIH
Xiaoping Zhu: University of Maryland

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10865-y

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