Human mitochondrial antiviral-signalling protein is required for innate immune defence against viruses. It acts downstream of DDX58/RIG-I and IFIH1/MDA5, which detect intracellular dsRNA produced during viral replication, to coordinate pathways leading to the activation of NF-kappa-B, IRF3 and IRF7, and to the subsequent induction of antiviral cytokines such as IFN-beta and RANTES (CCL5). It may activate the same pathways following detection of extracellular dsRNA by TLR3. It also may protect cells from apoptosis [, , , , ].
This family represents Protein K7 from Orthopoxvirus. K7 is Bcl-2-like protein which, through its interaction with the DEAD box RNA helicase DDX3X/DDX3, prevents TBK1/IKKepsilon-mediated IRF3 activation []. It contributes to virulence by binding to the host TRAF6 and IRAK2 and preventing host NF-kappa-B activation and affects the acute immune response to infection [, , ]. In vaccinia virus, this protein has been related to the increase in cellular histone methylation during infection [].
In humans, TASL (TLR adaptor interacting with SLC15A4 on the lysosome) is encoded by CXorf21 that is associated with systemic lupus erythematosus []. It is an immune adaptor that is required for recruitment and activation of IRF5 by TLR7, TLR8 and TLR9, in mechanistic analogy to IRF3 and its three adaptors STING, MAVS and TRIF. TASL interacts with the endolysosomal transporter SLC15A4; the SLC15A4-TASL complex is required for endolysosomal TLR signalling. TASL contains a pLxIS motif that is important for its function [].
RNA-binding protein E3 from Vaccinia virus (E3L) is a dsRNA-binding protein capable of inhibiting protein kinase R and is an effective IRF3 and -7 phosphorylation inhibitor []. The C terminus of E3L binds to double-stranded RNA (dsRNA), while the N terminus of E3L is required for the additional regulation of eIF2alpha phosphorylation [].Protein E3 from Variola virus is also included in this family. It plays a role in the inhibition of multiple cellular antiviral responses activated by dsRNA, such as inhibition of PKR activation, apoptosis, and IFN-mediated antiviral activities [].
RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination of MITA after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction []. Although RNF26 substrates of ubiquitination remain unclear at present, RNF26 upregulation in gastric cancer might be implicated in carcinogenesis through dysregulation of growth regulators [].RNF26 contains an N-terminal leucine zipper domain and a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain [].
This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of TRIM4 which is also known as RING finger protein 87 (RNF87). TRIM proteins are defined by the presence of the tripartite motif RING/B-box/coiled-coil region and also known as RBCC proteins []. TRIM4 is a positive regulator of RIG-I-mediated interferon (IFN) induction. It regulates virus-induced IFN induction and cellular antiviral innate immunity by targeting RIG-I for K63-linked poly-ubiquitination []. Over-expression of TRIM4 enhances virus-triggered activation of transcription factors IRF3 and NF-kappaB, as well as IFN-beta induction []. Expression of TRIM4 differs significantly in Huntington's Disease (HD) neural cells when compared with wild-type controls, possibly impacting down-regulation of the Huntingtin (HTT) gene, which is involved in the regulation of diverse cellular activities that are impaired in Huntington's Disease (HD) cells [].
Helicase nonstructural protein 13 (NSP13) is encoded by the replicase polyprotein 1a/ab of coronaviruses and released after a proteolytic process. It plays a vital role in catalysing the unwinding of duplex oligonucleotides into single strands in an NTP-dependent manner. It is a multidomain protein which includes an N-terminal Cys/His rich zinc-binding domain (ZBD), followed by a stalk and 1B domains, and a helicase core that belongs to the superfamily SF1 of helicases, containing two RecA1 and RecA2 domains [, ]. The stalk region connects the ZBD domain and 1B domain. Nsp13 adopts a triangular pyramid shape in which the two RecA1 and A2 and 1B domain form the triangular base, while N-terminal ZBD and stalk domains are arranged at the apex of the pyramid [, , ]. Recently, it has been reported that SARS-CoV-2 NSP13 as an interferon antagonist. It is involved in type I interferon (IFN-I) response as it binds and blocks TBK1 phosphorylation to inhibit interferon regulatory factor 3 (IRF3) which results in decreased IRF3 activation [, ].This entry represents the 1B domain, which has a regulatory role modulating the nucleic acid substrate binding. Based on the structures from the related Equine arteritis virus (EAV) NSP10, it is likely that 1B domain forms a channel together with 1A and 2A domains that accommodates the single stranded nucleic acids [, ].
