Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis

Yanyan Zheng; Qingxiang Liu; Yaoxing Wu; Ling Ma; Zhenzhen Zhang; Tao Liu; Shouheng Jin; Yuanchu She; Yi-Ping Li; Jun Cui

doi:10.15252/embj.201899347

Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis

EMBO J. 2018 Sep 14;37(18):e99347. doi: 10.15252/embj.201899347. Epub 2018 Jul 31.

Authors

Yanyan Zheng¹, Qingxiang Liu¹, Yaoxing Wu¹, Ling Ma², Zhenzhen Zhang², Tao Liu¹, Shouheng Jin¹, Yuanchu She¹, Yi-Ping Li^{3

4}, Jun Cui⁵

Affiliations

¹ MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
² Institute of Human Virology, Key Laboratory of Tropical Diseases Control Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
³ Institute of Human Virology, Key Laboratory of Tropical Diseases Control Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China lyiping@mail.sysu.edu.cn cuij5@mail.sysu.edu.cn.
⁴ Department of Infectious Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
⁵ MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China lyiping@mail.sysu.edu.cn cuij5@mail.sysu.edu.cn.

Abstract

Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non-structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11-linked poly-ubiquitin chains from caspase-1 at Lys134, thus inhibiting the proteasomal degradation of caspase-1. The enhanced stabilization of caspase-1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKVin vitro and in vivo Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future.

Keywords: Zika virus; antiviral immunity; inflammasome; type I interferon signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caspase 1 / genetics
Caspase 1 / immunology*
Chlorocebus aethiops
Endopeptidases / genetics
Endopeptidases / immunology
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / immunology
HEK293 Cells
Humans
Immune Evasion*
Inflammasomes / genetics
Inflammasomes / immunology
Inflammation / genetics
Inflammation / immunology
Inflammation / pathology
Inflammation / virology
Mice
Mice, Knockout
Nucleotidyltransferases / genetics
Nucleotidyltransferases / immunology*
Proteolysis*
Signal Transduction / genetics
Signal Transduction / immunology*
THP-1 Cells
Ubiquitin Thiolesterase / genetics
Ubiquitin Thiolesterase / immunology
Vero Cells
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / immunology*
Zika Virus / genetics
Zika Virus / immunology*

Substances

Endosomal Sorting Complexes Required for Transport
Inflammasomes
NS1 protein, zika virus
Viral Nonstructural Proteins
Nucleotidyltransferases
cGAS protein, human
cGAS protein, mouse
Endopeptidases
USP8 protein, human
Ubiquitin Thiolesterase
Usp8 protein, mouse
Caspase 1