Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I–Mediated Immune Signaling and Inhibit Host Antiviral Response

Abstract

Foot-and-mouth disease is a highly contagious disease of pigs, sheep, goats, bovine, and various wild cloven-hoofed animals caused by foot-and-mouth disease virus (FMDV) that has given rise to significant economic loss to global livestock industry. FMDV 3B protein is an important determinant of virulence of the virus. Modifications in 3B protein of FMDV considerably decrease virus yield. In the current study, we demonstrated the significant role of 3B protein in suppression of type I IFN production and host antiviral response in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells. We found that 3B protein interacted with the viral RNA sensor RIG-I to block RIG-I-mediated immune signaling. 3B protein did not affect the expression of RIG-I but interacted with RIG-I to block the interaction between RIG-I and the E3 ubiquitin ligase TRIM25, which prevented the TRIM25-mediated, Lys 63-linked ubiquitination and activation of RIG-I. This inhibition of RIG-I-mediated immune signaling by 3B protein decreased IFN-b, IFN-stimulated genes, and proinflammatory cytokines expression, which in turn promoted FMDV replication. All of the three nonidentical copies of 3B could inhibit type I IFN production, and the aa 17A in each copy of 3B was involved in suppression of IFN-related antiviral response during FMDV infection in porcine cells. Together, our results indicate the role of 3B in suppression of host innate immune response and reveal a novel antagonistic mechanism of FMDV that is mediated by 3B protein.

Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5

“…While RIG-I is essential for detecting infection of many negative-strand RNA viruses and some flaviviruses [ 15 , 16 , 17 , 18 ], MDA5 is critical for the recognition of the picornavirus, coronavirus and calicivirus families [ 19 , 20 , 21 ]. However, many studies have focused on RIG-I compared to MDA5 in relation to the FMDV of the family picornavirus [ 22 , 23 , 24 , 25 ], little is known about the interplay between MDA5 and FMDV.…”

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

“…RIG-I signalling mediated by TRIM25 and related E3 ligases is one of the key steps in the host response against a broad spectrum of RNA viruses, many of which pose a significant hazard for public health and human well-being, such as Influenza, Dengue, Ebola and the novel coronaviruses (1,2). Many of these viruses have developed host-pathogen interactions to evade host immunity by interfering with TRIM25mediated RIG-I ubiquitination (3)(4)(5)(6)(7)(8)(9). The recent outbreaks of emerging human pathogens such as Ebola in Western Africa in 2013-2016 or the ongoing SARS-CoV-2 pandemic, the steady rise in Dengue virus infections over the last 50 years as a consequence of human-made climate change, as well as the seasonal death toll caused by Influenza virus, which could be significantly increased in the event of a pandemic, highlight the importance of understanding these host-pathogen interactions as a potential target for fighting these diseases.…”

Bovine Delta Papillomavirus E5 Oncoprotein Interacts With TRIM25 and Hampers Antiviral Innate Immune Response Mediated by RIG-I-Like Receptors

“…In our study, MAVS expression levels did not vary significantly. Many viruses block RLR-mediated immune signalling thus inhibiting host antiviral response without modifying MAVS expression levels ( 48 ). It is conceivable that in our spontaneous model of PV infection, the marked reduction in the expression levels of RIG-I and MDA5 may be responsible for the loss of conformational changes thus compromising the activation of MAVS, which is necessary for activating and propagating the antiviral signalling cascade.…”