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J+Virol
2018 ; 92
(8
): ? Nephropedia Template TP
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NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3
Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC
Ubiquitination
#MMPMID29386291
Park HS
; Liu G
; Thulasi Raman SN
; Landreth SL
; Liu Q
; Zhou Y
J Virol
2018[Apr]; 92
(8
): ? PMID29386291
show ga
The inflammasome represents a molecular platform for innate immune regulation and
controls proinflammatory cytokine production. The NLRP3 inflammasome is comprised
of NLRP3, ASC, and procaspase-1. When the NLRP3 inflammasome is activated, it
causes ASC speck formation and caspase-1 activation, resulting in the maturation
of interleukin-1? (IL-1?). The NLRP3 inflammasome is regulated at multiple
levels, with one level being posttranslational modification. Interestingly,
ubiquitination of ASC has been reported to be indispensable for the activation of
the NLRP3 inflammasome. Influenza A virus (IAV) infection induces NLRP3
inflammasome-dependent IL-1? secretion, which contributes to the host antiviral
defense. However, IAVs have evolved multiple antagonizing mechanisms, one of
which is executed by viral NS1 protein to suppress the NLRP3 inflammasome. In
this study, we compared IL-1? production in porcine alveolar macrophages in
response to IAV infection and found that the 2009 pandemic H1N1 induced less
IL-1? than swine influenza viruses (SIVs). Further study revealed that the NS1 C
terminus of pandemic H1N1 but not that of SIV was able to significantly inhibit
NLRP3 inflammasome-mediated IL-1? production. This inhibitory function was
attributed to impaired ASC speck formation and suppression of ASC ubiquitination.
Moreover, we identified two target lysine residues, K110 and K140, which are
essential for both porcine ASC ubiquitination and NLRP3 inflammasome-mediated
IL-1? production. These results revealed a novel mechanism by which the NS1
protein of the 2009 pandemic H1N1 suppresses NLRP3 inflammasome
activation.IMPORTANCE Influenza A virus (IAV) infection activates the NLRP3
inflammasome, resulting in the production of IL-1?, which contributes to the host
innate immune response. ASC, an adaptor protein of NLRP3, forms specks that are
critical for inflammasome activation. Here, we report that the NS1 C terminus of
the 2009 pandemic H1N1 has functions to suppress porcine IL-1? production by
inhibiting ASC speck formation and ASC ubiquitination. Furthermore, the
ubiquitination sites on porcine ASC were identified. The information gained here
may contribute to an in-depth understanding of porcine inflammasome activation
and regulation in response to different IAVs, helping to further enhance our
knowledge of innate immune responses to influenza virus infection in pigs.
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