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. 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.

The low complexity regions in the C-terminus are essential for the subcellular localisation of Leishmania casein kinase 1 but not for its activity

“…Increasing evidence suggests that the manipulation of host cell CK1 signalling pathways by intracellular pathogens, either by exploiting host CK1 or by exporting the CK1 of the pathogen into the host cell might play an important role in infectious diseases [12] [13] [14] [15] [16]. Indeed, host CK1 pathways are vital for Mycobacterium [15].…”

Casein kinase 1α: biological mechanisms and theranostic potential

“…CK1α phosphorylates type I interferon receptor 1 (IFNAR1) at Ser535 and thereby induces its ubiquitination and degradation via recruitment of β-TrCP E3 ubiquitin ligase in response to endoplasmic reticulum stress as well as infection [ 137 , 138 ] by the protozoan Leishmania major or vesicular stomatitis virus (VSV) in human cells [ 137 ] and by infectious bursal disease virus in chicken [ 139 ]. Newly research have demonstrated that CK1α mediates degradation of IFNAR1 and type II IFN (IFN-γ) receptor 1 (IFNGR1) caused by hemagglutinin of influenza A virus (IAV) [ 140 ]. CK1α also acts as a specific host factor and is required for the spread of Listeria monocytogenes between cells, which occurs via formation of productive membrane protrusions [ 141 ].…”

Role of Post-translational Modifications in Influenza A Virus Life Cycle and Host Innate Immune Response

“…HA promotes the phosphorylation and polyubiquitination of IFNAR1, leading to an efficient degradation of IFNAR1 and attenuation of the type I IFN-induced antiviral signaling pathway (Xia et al, 2016). Furthermore, HA induces the degradation of type II IFN receptor 1 (IFNGR1), as well as of IFNAR1, resulting in the impairment of the cellular response to both types I and II IFNs (Xia et al, 2018). Mechanistically, the phosphorylation and ubiquitination of IFNGR1 and IFNAR1 mediated by the cellular kinase CK1α contribute to the HA-induced elimination of type I and type II IFN receptors (Xia et al, 2018).…”

“…Furthermore, HA induces the degradation of type II IFN receptor 1 (IFNGR1), as well as of IFNAR1, resulting in the impairment of the cellular response to both types I and II IFNs (Xia et al, 2018). Mechanistically, the phosphorylation and ubiquitination of IFNGR1 and IFNAR1 mediated by the cellular kinase CK1α contribute to the HA-induced elimination of type I and type II IFN receptors (Xia et al, 2018).…”