A novel role of HSP70 proteins in antiviral immune response

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Transcriptional induction of type I and III interferons (IFN) in response to non-self or atypical self-nucleic acids is a crucial step in the activation of antiviral innate immunity and inflammation, and a process that needs to be tightly controlled, as excessive and chronic IFN induction may lead to autoimmune diseases. In our previous work we have identified a so far not appreciated crucial role of the cellular HSP70 protein family in regulation of RIG-I like receptor-mediated IFN induction. Initially, HSP70 was identified as a direct target of the rabies virus phosphoprotein P, a potent IFN antagonist. Direct binding of P to HSP70 is mediated by a specific P peptide motif, and distinct from HSP70 substrate binding. Binding to HSP70 strictly correlates with the ability of P to shut down activation of the IFN transcription factor IRF3, as shown by mutagenesis of plasmid-expressed P and engineered recombinant viruses. Expression of selected HSP70 mutants strongly interferes with IFN induction by RIG-I, further confirming an intrinsic regulatory role in the control of IFN induction. In the present project we aim at specifying the novel role of heat shock and possibly multiple HSP70 members in regulation of the IFN response, and to clarify how viral proteins like P can exploit HSPs to prevent the antiviral host response. The studies involve mutational and pharmacological analyses of the pleiotropic HSP70 functions, and cell biological studies in the absence and presence of engineered P proteins. The results might allow devising novel strategies for antiviral treatment or immune suppression.