Abstract
Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.
Highlights
melanoma differentiation-associated protein 5 (MDA5) is modified by ISGylation at the caspase activation and recruitment domains (CARDs), which promotes MDA5 oligomerization and activation; SARS-CoV-2 PLpro physically interacts with MDA5 and inhibits its CARD ISGylation, suppressing MDA5-mediated antiviral immunity
This study revealed that the E96/E97 residues in nonstructural protein 1 (NS1), which are located in a highly conserved proteinprotein-interacting motif, were required for TRIM25 binding and efficient suppression of retinoic acid-inducible gene-I (RIG-I) CARD ubiquitination catalyzed by TRIM25 [39]
The papain-like proteases (PLPs) enzymes of other coronaviruses such as SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, murine hepatitis virus (MHV), and human coronavirus (HCoV)-NL63 were all able to bind to the MDA5 CARDs and to antagonize their ISGylation [22], suggesting that this immune evasion mechanism is widely conserved among coronaviruses, which warrants further investigation using authentic infection with these coronaviruses (Figure 1)
Summary
Infectious diseases caused by viruses affect the global population at an alarming rate, as can be seen by the current COVID-19 pandemic that has caused millions of infections worldwide. A number of PRRs have been discovered, each recognizing unique and defined PAMPs. This review focuses on the family of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), which sense cytoplasmic RNA. An increasing number of studies have, indicated that many RNA viruses are sensed by both RIG-I and MDA5 (Reviewed in [4]) Both RIG-I and MDA5 are DExD/H-box-containing helicases possessing two Nterminal caspase activation and recruitment domains (CARDs), a large helicase domain, and a carboxyl-terminal domain (CTD). These structural components are necessary for RNA binding and interacting with the common adaptor mitochondrial antiviral signaling protein (MAVS). IFN-induced effector proteins create a cellular milieu that is hostile to the virus, thereby dampening viral replication in the host organism and virus spread
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
