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Review
. 2017 Aug 22;5(3):23.
doi: 10.3390/vaccines5030023.

The TRIMendous Role of TRIMs in Virus-Host Interactions

Sarah van Tol  1 , Adam Hage  2 , Maria Isabel Giraldo  3 , Preeti Bharaj  4 , Ricardo Rajsbaum  5   6
Affiliations
Review

The TRIMendous Role of TRIMs in Virus-Host Interactions

Sarah van Tol et al. Vaccines (Basel). .

Abstract

The innate antiviral response is integral in protecting the host against virus infection. Many proteins regulate these signaling pathways including ubiquitin enzymes. The ubiquitin-activating (E1), -conjugating (E2), and -ligating (E3) enzymes work together to link ubiquitin, a small protein, onto other ubiquitin molecules or target proteins to mediate various effector functions. The tripartite motif (TRIM) protein family is a group of E3 ligases implicated in the regulation of a variety of cellular functions including cell cycle progression, autophagy, and innate immunity. Many antiviral signaling pathways, including type-I interferon and NF-κB, are TRIM-regulated, thus influencing the course of infection. Additionally, several TRIMs directly restrict viral replication either through proteasome-mediated degradation of viral proteins or by interfering with different steps of the viral replication cycle. In addition, new studies suggest that TRIMs can exert their effector functions via the synthesis of unconventional polyubiquitin chains, including unanchored (non-covalently attached) polyubiquitin chains. TRIM-conferred viral inhibition has selected for viruses that encode direct and indirect TRIM antagonists. Furthermore, new evidence suggests that the same antagonists encoded by viruses may hijack TRIM proteins to directly promote virus replication. Here, we describe numerous virus-TRIM interactions and novel roles of TRIMs during virus infections.

Keywords: E3-ubiquitin ligase; innate immunity; tripartite motif (TRIM); type-I interferons; ubiquitin; unanchored polyubiquitin; viral antagonism; virus infection.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of pattern recognition receptor (PRR) signaling by tripartite motifs (TRIMs). TRIMs play an integral role in the positive and negative regulation of antiviral pathways. TRIMs can act as pathogen PRRs, as is the case for TRIM21 in the recognition of non-enveloped viruses bound by immunoglobulin (Ig). Additionally, these TRIMs can regulate the activation of other PRRs that recognize viral pathogen-associated molecular patterns (PAMPs) in the cytosol (DDX41 (DEAD-box helicase 41), cyclic GMP-AMP synthase (cGAS), DEAH-box helicase 33 (DHX33), nucleotide-binding oligomerization domain-containing protein 2 (NOD2), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated protein (MDA5)) and at membrane surfaces (toll-like receptors, TLRs). Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family member-associated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors. This includes IFN regulatory factor (IRF)3 and IRF7, important in type-I interferon (IFN) signaling, and NF-κB, important in expression of pro-inflammatory genes, which regulate the expression of antiviral effectors. Type-I IFN production is critical for an effective antiviral response.
Figure 2
Figure 2
TRIMs in cytokine signaling. Downstream of the initial pathogen recognition and induction of pro-inflammatory cytokines, TRIMs can regulate their cytokine signaling pathways through interactions with cytokine receptor adaptors (TAB2/3) and enzymatic proteins (IKKα, IKKβ and IKKε) within the signaling complexes, the activity and stability of pathway negative regulators (Protein Inhibitor of Activated STAT 3 (PIAS3), suppressor of cytokine signaling (SOCS), and influence the transcription of various cytokine-effector genes (NF-κB-induced pro-inflammatory cytokines, signal transducer and activator of transcription (STAT)-induced genes, interferon stimulated genes (ISGs)) or cytokine signaling regulators (tumor necrosis factor (TNF) receptors (TNFR1/2, and STAT-induced genes)).
Figure 3
Figure 3
The role of TRIMs in retrovirus replication. TRIM5α oligomerization into a hexagonal lattice associates directly with HIV-1 capsids to promote premature uncoating. Recognition of HIV-1 capsid by TRIM5α also triggers NF-κB/AP-1-mediated innate immune signaling via synthesis of unanchored K63-linked poly-Ub chains that activate the TAK1 kinase. One potential mechanism of TRIM5α-mediated restriction could be involved ubiquitination of TRIM5α and proteasomal degradation of TRIM5α-capsid complexes. TRIM11 mobilizes cellular microtubule formation to prematurely uncoat HIV-1 and facilitate rapid release of the vRNA from the viral core, resulting in inhibition of virus replication. TRIM19 translocates to the cytoplasm and binds Daxx to prevent its degradation by the proteasome, allowing for Daxx-mediated disruption of HIV-1 reverse transcription (RT). TRIM22 inhibits Sp1, preventing LTR-mediated transcription. The connection between TRIM5α-mediated restriction and proteasomal-mediated degradation of HIV-1 requires further characterization. However, one potential model may involve improved proliferation of HIV-1-specific CD8+ T cells due to enhanced production of viral peptides from proteasome-mediated degradation of HIV-1 capsids.
Figure 4
Figure 4
Effects of TRIMs on influenza virus components and IFN antagonism. The TRIM25-binding domain of the viral NS1 protein prevents TRIM25-mediated activation of RIG-I. TRIM56 has been proposed to target viral 5’ triphosphate RNA and inhibit vRNA synthesis. TRIM22 targets the viral nucleoprotein, while TRIM32 prevents association of PB1 to the viral polymerase complex through K48-linked polyubiquitin chains that target the viral components for proteasome-mediated degradation.
Figure 5
Figure 5
The roles of TRIMs in flavivirus infection and innate immune antagonism. Flaviviruses are internalized by receptor-mediated endocytosis and by clathrin-mediated endocytosis (1). Fusion of virus membrane with host endosomal membrane (2). RNA genome is released into the cytoplasm (3). The positive-sense genomic ssRNA is translated into a polyprotein, which is cleaved into all structural and non-structural proteins (4). Replication takes place at the surface of endoplasmic reticulum in cytoplasmic viral factories (5). In this step, the TRIMs restrict virus replication, degrading viral proteins such as NS2A in Japanese encephalitis virus (JEV) by TRIM52 and viral RNA inhibition in JEV and Dengue virus (DENV) by TRIM56. TRIM22 and TRIM79 degrade NS5 protein in hepatitis C virus (HCV) and tick-borne encephalitis virus (TBEV), respectively. Virus assembly occurs at the endoplasmic reticulum. The virion buds at the endoplasmic reticulum and is transported to the Golgi apparatus (6). The prM protein is cleaved in the Golgi, thereby maturing the virion, which is fusion competent (7). Release of new virions by exocytosis (8). TRIMs and antagonism function also are used by flaviviruses. TRIM21 inhibits IFN-β production during JEV infection. TRIM23 promotes yellow fever virus replication. DENV short noncoding sfRNAs bind TRIM25 to inhibit IFN expression.
Figure 6
Figure 6
TRIM6 is targeted by Nipah and Ebola viruses to enhance virus replication. Ebola virus (EBOV) inhibits type-I IFN production by multiple mechanisms. EBOV VP35 binds and inhibits RIG-I, IKKε, and TBK-1 to inhibit IFN production. TRIM6 ubiquitinates VP35 on K309 and promotes VP35 activity as the cofactor of the viral polymerase and enhances virus replication. Additional unidentified ubiquitination sites of VP35 exist. Whether TRIM6 enhances EBOV replication by promoting viral genome replication or viral gene transcription is not known. In Nipah virus infection, the viral matrix protein (NiV-M) promotes TRIM6 degradation, resulting in reduced synthesis of K48-linked unanchored polyubiquitin chains, IKKε oligomerization, IKKε-T501 autophosphorylation, IRF3 phosphorylation, and reduced IFN induction. These combined losses confer an impaired host-antiviral response.
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