Abstract 1108 Tyrosine Phosphorylated Prion Protein binds TBK1 to Suppress RNA Virus Induced Innate Immunity

Tank-binding kinase 1 (TBK1) is one of the most pivotal effectors transducing the signal from the pattern recognition receptors (PRRs) triggered by the invading pathogens to phosphorylate interferon regulation factors. TBK1 activation is tightly regulated by the host to restrain the over-activation of the innate immunity. Prion protein (PrP) is an essential cellular factor for the development of prion disease whose physiological functions remain elusive. Here, using techniques of cell biology, immunology, biochemistry and molecular biology, we identify PrP as a negative regulator of type 1 interferon (IFN1) induced by RNA virus infection. Over-expression of PrP inhibits RNA virus induced activation of IFN whereas knockout of PrP has the opposite effects. Prnp-deficient mice produce much more IFNβ and inflammatory cytokines in response to VSV infection and are more resistant to VSV-induced death. Mechanistically, Src phosphorylates PrP at residue Y169 and maybe Y49 to allow phosphorylated-PrP interacting with the kinase domain of TBK1. As a result of PrP-TBK1 interaction, the binding between TBK1 and MAVS is reduced, leading to decreased dimerization and phosphorylation of IRF3. Accordingly, entry of IRF3 is mitigated resulting in reduced activation of IFN1 and inflammatory cytokine production. More importantly, phosphorylated-PrP is resistant to proteinase K (PK) treatment to some extent. α-fold2 simulation implies the PK resistance is due to potentially a loss of a helical structure normally formed around Y169 residue in the unphosphorylated-PrP.In conclusion, our findings suggest that phosphorylated-PrP may link virus infection to neurodegeneration. National Natural Science Foundation of China, MOST