The Roles of TRIMs in Antiviral Innate Immune Signaling

Abstract

The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins' role in the signaling pathway of antiviral innate immune response and the direct "game" between them.

Keywords: E3 ubiquitin ligase; direct game; innate immune response; signaling pathway; tripartite motif (TRIM).

Figure 1

The Ubiquitin-Proteasome System. The conjugation reaction of ubiquitin is catalyzed by the E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. E3 ubiquitin ligase could recognize substrates and transfer ubiquitin from E2 ubiquitin-conjugating enzymes to substrates, resulting in the proteasome degradation of the polyubiquitinated substrates.

Figure 2

The Domain Structure and the Classification of Tripartite Motif (TRIM) Family Proteins. (A) Domain structure of TRIM proteins. Most TRIM proteins possess conservative RBCC domains at the amino-terminus and diverse domains at the carboxyl-terminus. RBCC domains consist of a RING finger domain, a B-box 1 and/or B-box 2 domain, and a coiled-coil domain (CCD). (B) Classification of TRIM proteins. TRIM proteins with the RING domain are classified into 11 subfamilies from Class I to Class XI according to their distinctive C-terminal domains. Besides, there is an unclassified group lacking the RING domain (no RING). PRY, SPRY-associated domain; SPRY, SPIa and the ryanodine receptor domain; COS, C-terminal subgroup one signature domain; FN3, fibronectin type 3 domain; ACID, acid-rich region; PHD, plant homeodomain; BROMO, bromodomain; FIL, filamin-type IG domain; NHL, NHL repeats; MATH, meprin, and tumor necrosis factor receptor-associated factor (TRAF) homology domain; ARF, ADP-ribosylation factor family domain; TM, transmembrane region. Numbers indicate individual TRIM proteins.

Figure 3

TRIM-mediated regulation of innate immune signaling pathways. TRIM proteins play a dual role in antiviral immune signaling pathways indicated by black arrows. They could positively or negatively regulate antiviral immune signaling pathways, indicated by green arrows or red lines, respectively. Also, some TRAM proteins can act as common pathogen PRRs, or as cytosolic Fc receptors (such as TRIM21) to recognize non-enveloped viruses bound by immunoglobulin (Ig). DDX41, DEAD-box helicase 41; cGAS, cyclic GMP-AMP synthase; DHX33, DEAH-box helicase 33; NOD-2, nucleotide-binding oligomerization domain-containing protein 2; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein; TLR, Toll-like receptors; STING, stimulator of IFN genes; MAVS, mitochondrial antiviral signaling protein; TAK1, TGF-β-activated kinase 1; TAB2, TAK1/MAP3K7-binding protein 2; MyD88, Myeloid differentiation primary response gene 88; TRIF, TIR-domain-containing adapterinducing interferon-β; NEMO, NF-κB essential modulator; NAP-1, nucleosome assembly protein; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factors; TANK, TANK-binding kinase 1; IκB, inhibitor of NF-κB; IKK, IκB kinase; TBK1, TANK binding kinase 1; IFN, interferon; IRF, interferon regulatory factor; P, phosphorylation; Ub, ubiquitin; dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; ssRNA, single-stranded; ADV, adenovirus; IL, interleukin; AP-1, activator protein-1; PIN1, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; ECSIT, evolutionarily conserved signaling intermediate in Toll pathway; CASPASE-1, cysteinyl aspartate specific proteinase 1; β-TrCP, β-transducinrepeats containing proteins.

Figure 4

The NS1 protein of RSV or IAV prevents TRIM25-mediated activation of the RLR signaling pathway. IAV, influenza A virus; RSV, respiratory syncytial virus; NS1, nonstructural protein 1.

Figure 5

Viruses “domesticate” TRIM proteins for their replications. VP35 protein of Ebola virus (EBOV) could serve as an essential cofactor of the viral polymerase, and a potent antagonist of RIG-I mediated innate immunity. TRIM6 can be recruited to ubiquitinate VP35 protein on K309, promoting virus replication by enhancing viral polymerase activity or decreasing its ability to antagonize RIG-I mediated innate immunity.