TRIM Proteins and Their Roles in Antiviral Host Defenses

Abstract

Tripartite motif (TRIM) proteins are a versatile family of ubiquitin E3 ligases involved in a multitude of cellular processes. Studies in recent years have demonstrated that many TRIM proteins play central roles in the host defense against viral infection. While some TRIM proteins directly antagonize distinct steps in the viral life cycle, others regulate signal transduction pathways induced by innate immune sensors, thereby modulating antiviral cytokine responses. Furthermore, TRIM proteins have been implicated in virus-induced autophagy and autophagy-mediated viral clearance. Given the important role of TRIM proteins in antiviral restriction, it is not surprising that several viruses have evolved effective maneuvers to neutralize the antiviral action of specific TRIM proteins. Here, we describe the major antiviral mechanisms of TRIM proteins as well as viral strategies to escape TRIM-mediated host immunity.

Keywords: TRIM protein; antiviral restriction; innate immunity; interferon; virus infection.

Figure 1

Domain structure of tripartite motif (TRIM) proteins. The TRIM, consisting of a really interesting new gene (RING) domain, a B-box 1 and/or B-box 2 domain, and a coiled-coil domain (CCD), is followed by distinct C-terminal domains: SPRY-associated domain (PRY), SPIa and the ryanodine receptor domain (SPRY), C-terminal subgroup one signature domain (Cos), fibronectin type 3 domain (FN3), plant homeodomain (PHD), bromodomain (BROMO), acid-rich region (AR), filamin domain, NHL repeats (NHL), transmembrane domain (TM), ADP-ribosylation factor domain (ARF), and meprin and tumor necrosis factor receptor–associated factor homology domain (MATH). Numbers indicate individual TRIM proteins.

Figure 2

TRIM-mediated regulation of innate immune signaling pathways. Overview of the TRIM proteins (blue) that positively (green arrows) or negatively (red lines) regulate (a) PRR-mediated induction of type I IFNs and proinflammatory cytokines or (b) IFNAR-induced expression of ISGs. Intracellular receptors are illustrated in red. Signaling intermediates or transcription factors are illustrated in green. Abbreviations: cGAS, cyclic GMP-AMP synthase; 27, K27-linked polyubiquitination; 48, K48-linked polyubiquitination; 63, K63-linked polyubiquitination; IFN, interferon; IFNAR, IFNα/β receptor; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated protein 5; PRR, pattern-recognition receptor; RIG-I, retinoic acid-inducible gene-I; STAT, signal transducer and activator of transcription; STING, stimulator of interferon genes; SUMO, SUMOylation; TLR, Toll-like receptor; TRIM, tripartite motif protein; USP, ubiquitin-specific peptidase, WHIP, Werner helicase interacting protein 1.

Figure 3

Direct antiviral effects of TRIM proteins. (a) TRIM5α restricts retroviral infection by directly interacting with the viral capsid and inducing premature uncoating and capsid disassembly. This process may release viral PAMPs that can be sensed by cytosolic PRRs. Both proteasomal and autophagic degradative mechanisms have been implicated in TRIM5α-mediated virus restriction. In addition, TRIM5α catalyzes noncovalent K63-linked ubiquitin chains that activate the TAK1 signaling complex and thereby activate NF-κB and AP1. TRIM21 is a cytosolic sensor of antibody-opsonized, nonenveloped RNA and DNA viruses. Proposed antiviral mechanisms for TRIM21 include proteasomal degradation of incoming viral particles; activation of signaling pathways leading to NF-κB, AP1, and IRF activation; and release of viral PAMPs for detection by RIG-I or cGAS and potentially other intracellular PRRs. (b) Several TRIM proteins directly interfere with IAV replication. TRIM22 induces proteasomal degradation of the viral nucleoprotein NP. In the nucleus, TRIM32 induces proteasomal degradation of the viral polymerase subunit PB1, while TRIM25 interacts with vRNPs to prevent the viral polymerase from accessing the viral RNA template. TRIM56 blocks IAV RNA synthesis through an unknown mechanism. Solid lines indicate direct or well-established interactions. Dashed lines indicate indirect correlations. Abbreviations: 48, K48-linked polyubiquitination; cGAS, cyclic GMP-AMP synthase; IAV, influenza A virus; IFN, interferon; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; TRIM, tripartite motif protein; vRNP, viral ribonucleoprotein.

Figure 4

TRIM proteins regulating virus-induced autophagy. TRIM proteins can promote viral autophagy in at least two different ways. For example, TRIM23 (panel a) activates key molecules of the autophagic machinery, whereas TRIM5α (panel b) recognizes and recruits viral cargo to the autophagic machinery for degradation. (a) The E3 enzymatic activity of TRIM23 is activated upon infection by diverse viral pathogens (e.g., HSV-1, SINV), which leads to nondegradative K27-linked autopolyubiquitination of its C-terminal ARF domain. K27-linked ubiquitination in turn stimulates ARF GTPase activity. Upon recruitment of TBK1 to the ARF domain of TRIM23, ubiquitin-induced GTP-GDP cycling of the ARF domain facilitates TBK1 dimerization and trans−autophosphorylation and thereby promotes activation of TBK1’s catalytic activity. TBK1-mediated phosphorylation of the autophagy receptor p62 enables viral cargo recognition by p62 and ultimately causes degradation of the cargo. (b) TRIM5α recognizes the capsid protein of HIV-1 (p24), causing premature virus uncoating, which blocks HIV-1 infection. At least two destructive mechanisms reportedly lead to p24 degradation: the proteasome (not illustrated) and autophagic degradation. Autophagy is induced by the p24-TRIM5α complex in a Beclin-1- and ULK1-dependent manner at budding autophagosomes, ultimately leading to p24 degradation. Abbreviations: ARF, ADP-ribosylation factor; HIV-1, human immunodeficiency virus type 1; HSV-1, herpes simplex virus type 1; RING, really interesting new gene; SINV, Sindbis virus; SPRY, SPIa and the ryanodine receptor; TRIM, tripartite motif protein; Ub, ubiquitin.