#EV71 inhibits #pyroptosis through cleavage of GSDMD (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Enterovirus 71 inhibits pyroptosis through cleavage of GSDMD

Xiaobo Lei1, Zhenzhen Zhang1, Xia Xiao1, Jianli Qi1, Bin He2* and Jianwei Wang1,3*

Author Affiliations: 1 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China; 2 Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612, USA; 3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, Zhejiang Province, China.

 

ABSTRACT

Enterovirus 71 (EV71) can cause hand, foot, and mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remain poorly understand. Here, we report that EV71 induces degradation of GSDMD, an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1-193. However, unlike the N-terminal fragment produced by casaspe-1 cleavage, this fragment fails to trigger cell death or inhibits EV71 replication. Importantly, T239D or F240D substitution abrogates the activity of GSDMD composed of amino acids 1-275. This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.

 

IMPORTANCE

Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated IL-1β secretion. In this process, the N-terminal domain p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection down-regulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N—terminal fragment disrupted for inducing cell pyroptosis. Notably, the 1-275aa fragment (p30) inhibits EV71 replication whereas the 1-193aa fragment does not. These results reveal a new strategy for EV71 to evade the antiviral response.

 

FOOTNOTES

*Correspondence and requests for materials should be addressed to J.W. (email: wangjw28@163.com) or B.H. (email: tshuo@uic.edu)

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: EV71; HFMD.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.