Rabies virus matrix protein hijacks the TGF-beta activated kinase 1 binding protein 2-p38 mitogen-activated protein kinase pathway to inhibit apoptosis and promote viral replication.

Rabies virus (RABV) is a neurotropic virus that infects nearly all warm-blooded mammals and is almost invariably fatal once symptoms appear. Previous studies indicate that RABV uses its structural proteins to hijack host factors or modulate host signaling pathways to promote viral replication and pathogenicity. In this study, we observed upregulated expression of the host factor TGF β activated kinase 1 binding protein 2 (TAB2) in N2a cells following RABV infection. Loss and gain of function experiments confirmed that TAB2 overexpression enhances RABV replication, whereas TAB2 knockout suppresses it. We further demonstrated that TAB2 promotes RABV replication by activating the TGF β activated kinase 1 (TAK1)-p38 mitogen activated protein kinase (MAPK) signaling pathway. Co immunoprecipitation assays revealed an interaction between endogenous TAB2 and RABV M protein during infection. Further mapping showed that two TAB2 domains (aa 51-574 and aa 575-693) mediate this interaction; however, only the C terminal region (aa 575-693)-which contains ubiquitin modification sites and mediates TAK1 binding-is essential for the proviral function of TAB2. Mechanistically, early in RABV infection, M protein interacts with TAB2 and inhibits its K48 linked ubiquitination, leading to TAB2 stabilization and enhanced assembly of the TAB2-TAK1 complex. This process suppresses apoptosis via activation of the TAK1-p38/MAPK pathway and ultimately facilitates viral replication. These findings were corroborated in a TAB2 knockdown mouse infection model. Our study reveals a mechanism by which RABV M protein hijacks the host TAB2-TAK1-p38/MAPK signaling axis to inhibit apoptosis at early stage of infection, highlighting potential therapeutic targets for rabies intervention.