Abstract
The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3−/− mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNβ), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3′s RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies.
Highlights
We have shown that a linear ubiquitination-mediated posttranslational modification of Interferon regulatory factor 3 (IRF3) triggers the virus-induced apoptotic pathway by receptor-induced IRF3 mediated pathway of apoptosis (RIPA) [48]
We showed that the deacetylation of the IRF3 coactivator β-catenin by HDAC6 facilitates the formation of a stable transcription initiation complex in Toll-like receptors (TLRs)/RIG-I-like receptors (RLRs) signaling; acetylation of IRF3 itself was not observed [41]
Posttranslational modifications of IRF3 by cellular and viral proteins are critical for the outcome of the host-virus interaction
Summary
IRF3 belongs to the interferon regulatory factor (IRF) family of transcription factors, which consists of nine members in mammalian cells [1,2]. IRFs have diverse cellular roles, including innate immunity, cell cycle progression, apoptosis, and tumor suppression [2,3] These distinct functions are conferred by the activity of specific domains of the protein that allow it to form homo and heterodimers, which interact with other transcription factors or possess intrinsic transactivation potential [4,5]. IRF3 functions are regulated by posttranslational modifications (PTMs), e.g., phosphorylation, ubiquitination, and others, which alter protein conformation to relieve autoinhibition or allow interactions with additional binding partners. Such regulation is tightly controlled to avoid excessive inflammation and maintain cellular immune homeostasis. We describe how coronaviruses, including the SARS-CoV-2, antagonize the activation of IRF3
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