RNA‐virus proteases counteracting host innate immunity

Abstract

Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

“…Ub and ISG15 are important for innate antiviral immunity (Heaton et al, 2016;Morales and Lenschow, 2013); therefore, viruses tend to not only inhibit the conjugation of Ub or ISG15 to targets but also remove Ub or ISG15 from ubiquitinated or ISGylated proteins, respectively (Yuan and Krug, 2001;Bakshi et al, 2013;Yang et al, 2014). Thus, in CoVs, one or two papain-like protease (PL pro ) domain(s) within Nsp3 possess deubiquitinating (DUB) and deISGylating activities (see below; for a recent review on the role of viral proteases in counteracting the host-cell's innate immune system, see Lei and Hilgenfeld (2017)). Interestingly, two ubiquitin-like domains (Ubl1 and Ubl2) exist in all CoVs (see below ;Neuman, 2016).…”

“…Among these, the coronavirus PL2 pro should select its specific targets, such as the host innate-immune system-related proteins TRAF3, STING, TBK1, IRF3 etc. Lei and Hilgenfeld, 2017), with the goal of facilitating efficient virus survival. We therefore speculate that the Ubl2 might act as a modulator helping the PL2 pro recognize its specific targets during coronavirus infection.…”

“…The DUB and deISGylating activities of CoV PL pro s are well established, but the detailed mechanism of the PL pro antagonism of the host innate immune response is still ambiguous (see Lei and Hilgenfeld, 2017, for a recent review). Various cytokines (including interferons (IFNs) and tumor necrosis factors (TNFs)) are produced to inhibit virus replication by two main pathways, the IRF3 pathway and the NF-κB pathway (Seth et al, 2006;Hiscott et al, 2006).…”

“…Various cytokines (including interferons (IFNs) and tumor necrosis factors (TNFs)) are produced to inhibit virus replication by two main pathways, the IRF3 pathway and the NF-κB pathway (Seth et al, 2006;Hiscott et al, 2006). For more information on the host innate immune system signaling pathways, the reader should consult other reviews (e.g., Mogensen, 2009;Lei and Hilgenfeld, 2017). Devaraj et al (2007) found that the SARS-CoV PL2 pro can directly bind IRF3 to block its phosphorylation, dimerization, and nuclear translocation, thereby inhibiting IFN-β induction.…”

The deubiquitinating activity of Middle East respiratory syndrome coronavirus papain-like protease delays the innate immune response and enhances virulence in a mouse model

“…Many viral proteases with a primary role in virus replication have evolved to target host cell proteins, and often these accessory cleavage events indirectly affect viral replication and pathogenesis (77). Coronaviral PL pro s constitute a striking example of this kind of dual functionality, as they not only cleave multiple sites in the replicase polyproteins of which they are part, but can also deconjugate Ub, and Ub-like modifiers such as ISG15, presumably to suppress innate immune responses (55).…”