J Virol. 2018 Mar 14;92(7). pii: e00006-18. doi: 10.1128/JVI.00006-18. Print 2018 Apr 1.
Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus.
Abstract
Although
influenza A virus (IAV) evades cellular defense systems to effectively
propagate in the host, the viral immune-evasive mechanisms are
incompletely understood. Our recent data showed that hemagglutinin (HA)
of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor
1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting
in the impairment of cellular responsiveness to both type I and II IFNs.
IAV infection or transient HA expression induced degradation of both
IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate
the receptors. IAV HA caused the phosphorylation and ubiquitination of
IFNGR1, leading to the lysosome-dependent degradation of IFNGR1.
Influenza viral HA strongly decreased cellular sensitivity to type II
IFNs, as it suppressed the activation of STAT1 and the induction of
IFN-γ-stimulated genes in response to exogenously supplied recombinant
IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2,
was proven to be critical for HA-induced degradation of both IFNGR1 and
IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA
(siRNA)-based knockdown of CK1α repressed the degradation processes of
both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was
shown to be pivotal for proficient replication of IAV. Collectively, the
results suggest that IAV HA induces degradation of IFN receptors via
CK1α, creating conditions favorable for viral propagation. Therefore,
the study uncovers a new immune-evasive pathway of influenza virus.IMPORTANCE
Influenza A virus (IAV) remains a grave threat to humans, causing
seasonal and pandemic influenza. Upon infection, innate and adaptive
immunity, such as the interferon (IFN) response, is induced to protect
hosts against IAV infection. However, IAV seems to be equipped with
tactics to evade the IFN-mediated antiviral responses, although the
detailed mechanisms need to be elucidated. In the present study, we show
that IAV HA induces the degradation of the type II IFN receptor
IFNGR1 and thereby substantially attenuates cellular responses to
IFN-γ. Of note, a cellular kinase, casein kinase 1α (CK1α), is crucial
for IAV HA-induced degradation of both IFNGR1 and IFNAR1. Accordingly,
CK1α is proven to positively regulate IAV propagation. Thus, this study
unveils a novel strategy employed by IAV to evade IFN-mediated antiviral
activities. These findings may provide new insights into the interplay
between IAV and host immunity to impact influenza virus pathogenicity.
Copyright © 2018 American Society for Microbiology.
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