Foot-and-Mouth Disease Virus Capsid Protein VP1 Interacts with Host Ribosomal Protein SA To Maintain Activation of the MAPK Signal Pathway and Promote Virus Replication

Abstract

Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease, a highly contagious, economically important viral disease. The structural protein VP1 plays significant roles during FMDV infection. Here, we identified that VP1 interacted with host ribosomal protein SA (RPSA). RPSA is a viral receptor for dengue virus and classical swine fever virus infections. However, the incubation of susceptible cells using the anti-RPSA antibodies did not block the infection of FMDV. Overexpression of porcine RPSA in the insusceptible cells could not trigger FMDV infection, suggesting that RPSA was not responsible for FMDV entry and infection. On the contrary, we found that overexpression of RPSA suppressed FMDV replication, and knockdown of RPSA enhanced FMDV replication. We further determined that FMDV infection activated the mitogen-activated protein kinase (MAPK) pathway and demonstrated that MAPK pathway activation was critically important for FMDV replication. RPSA negatively regulated MAPK pathway activation during FMDV infection and displayed an antiviral function. FMDV VP1 interacted with RPSA to abrogate the RPSA-mediated suppressive role in MAPK pathway activation. Together, our study indicated that MAPK pathway activation was required for FMDV replication and that host RPSA played a negatively regulatory role on MAPK pathway activation to suppress FMDV replication. FMDV VP1 bound to RPSA to promote viral replication by repressing RPSA-mediated function and maintaining the activation of MAPK signal pathway. IMPORTANCE Identification of virus-cell interactions is essential for making strategies to limit virus replication and refine the models of virus replication. This study demonstrated that FMDV utilized the MAPK pathway for viral replication. The host RPSA protein inhibited FMDV replication by suppressing the activation of the MAPK pathway during FMDV infection. FMDV VP1 bound to RPSA to repress the RPSA-mediated regulatory effect on MAPK pathway activation. This study revealed an important implication of the MAPK pathway for FMDV infection and identified a novel mechanism by which FMDV VP1 has evolved to interact with RPSA and maintain the activation of the MAPK pathway, elucidating new information regarding the signal reprogramming of host cells by FMDV.

Selective regulation in ribosome biogenesis and protein production for efficient viral translation

“…HIV-1 Tat inhibits cell proliferation via an interaction with RPS3 and increases the level of RPS3 in the nucleus, thereby disrupting mitotic spindle formation during HIV-1 infection (Kim and Kim 2018 ). FMDV VP1 inhibits the antiviral response of RPSA by interacting with RPSA to promote FMDV replication (Zhu et al 2019 ). Binding of viral proteins to specific RPs plays a crucial role in viral infection.…”

Advances in Foot-and-Mouth Disease Virus Proteins Regulating Host Innate Immunity

“…Studies has shown that DNAJA3 can significantly reduce the inhibitory effect of VP1 on SeV-induced IRF3 phosphorylation, dimerization, and nuclear localization through the lysosomal pathway, thus reducing the antagonism on the IFN-β signal pathway and inhibiting FMDV replication ( Zhang et al, 2019 ). In addition, VP1 can also act on ribosomal protein SA (RPSA) to weaken its inhibitory effect on the mitogen-activated protein kinase (MAPK) pathway, which is conducive to the FMDV replication ( Zhu et al, 2020 ). VP2 may indirectly inhibit the host’s type I IFN response pathway by interacting with the host protein heat shock protein family B [small] member 1 (HSPB1) to enhance viral replication, but the mechanism needs to be further elucidated ( Sun et al, 2018 ).…”

Molecular Mechanisms of Immune Escape for Foot-and-Mouth Disease Virus

“…Another study suggested that the activation of the mitogen-activated protein kinase (MAPK) pathway is essential for FMDV replication. FMDV VP1 interacts with host ribosomal protein SA (RPSA) to continually activate the MAPK signal pathway and promote virus replication by inhibiting the RPSA-mediated function [59] (Figure 2, Table 1).…”

“…Ribosomal protein SA VP1 interacts with RPSA to maintain the activation of MAPK signal pathway and promote virus replication [59].…”