The New Function and Molecular Mechanism of LRP-receptor Associated Protein (RAP) Used by Viruses to Evade Host Cell's Innate Immunity

病毒利用LRP受體相關蛋白(RAP)的新功能和分子機制逃避宿主細胞的先天免疫系統

Student thesis: Doctoral Thesis

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Award date4 Jan 2021

Abstract

Type I interferons (IFN) signaling pathway is one of the most essential systems of innate immunity to defense pathogen attack. Though lipid metabolisms participate in the regulation of immune system, the interaction between lipoprotein metabolism and type I IFN signaling has not been discussed before. In this study, I found that enterovirus 71 (EV-A71) 2A protease can facilitate the expression of low-density lipoprotein receptor-related protein-associated protein 1 (RAP)-a host chaperon-like protein that is involved in the transportation in lipoprotein metabolism - to promote virus infection both in vivo and in vitro. Furthermore, both EV-A71 infection and 2A expression can increase the secretion of RAP in the extracellular environment. The secreted RAP dominates the virus entry, uncoating and infection. This promotion of viral infection is associated with the regulation of IFNAR1 protein expression by the secretion of RAP. Specifically, the extracellular RAP predominates the expression of IFNAR1 both in vivo and in vitro. On the contrary, RAP knockdown protects the expression of IFNAR1 in cells under the transfection of 2A protease or EV-A71 infection. Importantly, extracellular RAP can interact with the IFNAR1 on the cell surface and induce endocytosis, ensuing the lysosomal-dependent IFNAR1 degradation. These finding firstly indicates an interaction between lipoprotein metabolism pathway and type I IFN signalling response, and it also reveals a novel viral strategy to circumvent the anti-viral innate immunity via a secretion manner.

By estimating the expression and secretion of RAP from other viral infection models, the promotion of RAP expression and secretion may be a conservative strategy for several viruses, such as herpes simplex virus type 1 (HSV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to escape the type I IFN signalling pathway. Furthermore, extracellular RAP can promote multiple viral infections, including hepatitis B virus (HBV), HSV, ZIKV virus (ZIKV), influenza A virus subtype H3N1 and coronavirus 229E (CoV229E); while knock-down RAP can effectively protect cells from virus attack. Consequently, the inhibition of RAP acts as a universal antagonist for multiple viruses’ infection. To further optimize this universal anti-virus method, I found that an inhibitor targeting the extracellular RAP, alpha-2-macroglobulin (A2M), can effectively protect cells even after viral infection. Remarkably, these findings reveal that RAP-induced IFNAR1 inhibition can be broadly applied by multiple viruses’ infection. On the other hand, the inhibition of extracellular RAP is a promising target for anti-virus drug development and viral disease treatment.