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J Virol. 2017 Aug 24;91(18). pii: e01069-17. doi: 10.1128/JVI.01069-17. Print 2017 Sep 15.

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D.

Author information

1
MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA tshuo@uic.edu wangjw28@163.com.
3
MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China tshuo@uic.edu wangjw28@163.com.
4
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 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 remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (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 to 193 (GSDMD1-193). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD1-275). 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 interleukin-1β (IL-1β) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD1-275 (p30) inhibits EV71 replication whereas GSDMD1-193 does not. These results reveal a new strategy for EV71 to evade the antiviral response.

KEYWORDS:

3C; EV71; GSDMD; HFMD

PMID:
28679757
PMCID:
PMC5571240
[Available on 2018-02-24]
DOI:
10.1128/JVI.01069-17
[Indexed for MEDLINE]
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