The induction of type 1 interferon (IFN) antiviral response via the cytoplasmic, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs, RIG-I and MDA5) is a hallmark of the early host intrinsic immune responses to viral infections in a majority of cell types. It confers immediate antiviral restriction and orchestrates the development of subsequent adaptive immunity. This process is tightly regulated to ensure mounting timely defense to viral insults while limiting harmful, excessive inflammatory responses. Elucidating the regulatory mechanisms of RLR-mediated antiviral signaling not only helps understand host protective responses against invading viruses and pathogenesis of viral infectious diseases, but also may provide crucial clues that aid the design of safe and effective antiviral strategies. Autophagy is a homeostatic cellular process in which cytoplasmic materials, including macromolecules, organelles, and sometimes invading pathogens, are sequestered and delivered to lysosome for degradation. Recent evidence has suggested roles for autophagy or autophagy-related proteins in orchestrating immunity and host responses to microbial infections, but current knowledge on cellular kinases that regulate both autophagy and innate antiviral defense falls short. In preliminary studies we have identified SRMS (Src-related kinase lacking C-terminal regulatory tyrosine and N- terminal myristylation sites), a poorly characterized non-receptor tyrosine kinase, as a novel inhibitor of autophagy and a molecule pivotal for virus-induced IFN response via the RLR pathway. However, the underlying mechanisms are elusive. We hypothesize that SRMS is a novel player in innate antiviral defense by facilitating RLR-dependent signaling and/or through regulating the autophagy pathway.
Two specific aims are proposed to test this hypothesis.
In Aim 1, we will investigate the molecular determinants and mechanism that govern the contribution of SRMS to the RLR signaling pathway leading to IFN-regulatory factor-3 (IRF3) activation.
In Aim 2, we will define the the domain(s) and residue(s) of SRMS important for interaction with, phosphorylation of Beclin1 and autophagy restriction and determine the relationship between SRMS-mediated autophagy regulation and its effect on RLR-dependent innate antiviral responses. Completion of these studies will yield key insights into the novel role of SRMS in innate antiviral immunity, and may lead to identification of new targets/pathways that can be harnessed for developing broad-spectrum antiviral interventions for viral infectious diseases.
The proposed studies will yield new knowledge on how SRMS, a protein kinase expressed by host cells, contributes to cellular intrinsic antiviral defense mechanisms that fend off invading viruses. Completion of the project may lead to new targets or pathways that can be harnessed for developing novel, broad- spectrum antiviral interventions for controlling viral infectious diseases.
