Journal
EMBO JOURNAL
Volume 37, Issue 18, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899347
Keywords
antiviral immunity; inflammasome; type I interferon signaling; Zika virus
Categories
Funding
- National Key Basic Research Program of China [2015CB859800, 2014CB910800, 2015CB554301]
- National Natural Science Foundation of China [31522018, 91629101, 31470263, 31700150]
- Science and Technology Planning Project of Guangdong Province, China [2016A020219003]
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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 ZIKV in 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.
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