Rabies virus matrix protein hijacks the TAB2-TAK1-p38 MAPK pathway to inhibit apoptosis and promote viral replication

Rabies virus (RABV) is a neurotropic virus that infects nearly all warm-blooded mammals, with almost 100% fatality after symptoms appear. Studies have shown that RABV utilizes its structural proteins hijacking host factors or regulate host signaling pathways to facilitate viral replication and pathogenicity. In this study, we found that the expression of host factor TAK1-binding protein 2 (TAB2) was upregulated in N2a cells after RABV infection. Through loss- and gain-of-function experiments, we confirmed that the overexpression of TAB2 facilitated RABV replication and the knockout of TAB2 inhibited RABV replication. We further demonstrated that TAB2 promoted RABV replication by activating the TAK1-p38 MAPK signaling pathway. CO-IP results indicated that endogenous TAB2 interacted with RABV M protein during viral infection. Further studies confirmed that two domains of TAB2, 51-574aa and 575-693aa, were responsible for its interaction with M. However, only the 575-693aa domain of TAB2, containing the ubiquitin modification sites and mediating its binding to TAK1, was key for its pro-viral function. Mechanistically, during the early stages of RABV infection, M inhibited the K-48 ubiquitination of TAB2 by interacting with it, which facilitated the accumulation of TAB2 and subsequently enhanced the formation of the TAB2-TAK1 complex. This process inhibited apoptosis through the activation of the TAK1-p38/MAPK signaling pathway, ultimately promoting viral replication. This mechanism was also confirmed in the TAB2 knockdown mouse infection model. Our findings revealed the role of RABV M in hijacking the host TAB2-TAK1-p38 MAPK signal pathway to inhibit the apoptosis at early stage of infection, providing potential therapeutic targets against rabies.