Thursday, November 21, 2024
11/21/2024
Abstract: Herpesvirus infection is a major public health problem. Herpes Simplex virus-1 (HSV-1) is the prototype member of alpha-herpesvirus family. In additional to causing high morbidity and mortality in oral and neuronal infection in humans, HSV-1 is the leading etiological agent for infection-caused ocular keratitis and blindness for humans. To establish infection and escape critical components of the immune systems to remain latent in host cells, HSV-1 has evolved sophisticated immune evasion strategies. CD1d-restricted innate-like NKT cells play critical anti-microbial functions against different pathogens, including viruses, bacteria, fungi, and parasites. However, it remains unclear how HSV-1 evades the potent anti-microbial functions of NKT cells during infection and latency. We have discovered that HSV-1 rapidly and efficiently down-regulates CD1d from the surface of antigen- presenting cells. US3 is the primary viral gene responsible for this immune evasion function. Through phosphorylation, the US3 kinase targets the major cellular motor protein, KIF3A to inhibit the retrograde endosmal trafficking that mediates CD1d recycling to cell surface. We have identified three new phosphorylation sites in KIF3A by US3 kinase. We will delineate the molecular function of each phosphorylation event in suppressing the folding, assembly, and motor function of KIF3A to rapidly shut down KIF3A-mediated transport and inhibit CD1d surface expression. Successful outcome of this proposal will significantly impact our understanding of herpesvirus-mediated immune evasion as well as provides novel insights for functional mechanism of key motor protein KIF3A and its importance in immune evasion of CD1d.
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