TRIM Proteins in Host Defense and Viral Pathogenesis

Abstract

Purpose of Review Tripartite motif (TRIM) proteins are a large group of E3 ubiquitin ligases involved in different cellular functions. Of special interest are their roles in innate immunity, inflammation, and virus replication. We discuss novel roles of TRIM proteins during virus infections that lead to increased pathogenicity. Recent Findings TRIM proteins regulate different antiviral and inflammatory signaling pathways, mostly by promoting ubiquitination of important factors including pattern recognition receptors, adaptor proteins, kinases, and transcription factors that are involved in type I interferon and NF-κB pathways. Therefore, viruses have developed mechanisms to target TRIMs for immune evasion. New evidence is emerging indicating that viruses have the ability to directly use TRIMs and the ubiquitination process to enhance the viral replication cycle and cause increased pathogenesis. A new report on TRIM7 also highlights the potential pro-viral role of TRIMs via ubiquitination of viral proteins and suggests a novel mechanism by which ubiquitination of virus envelope protein may provide determinants of tissue and species tropism. Summary TRIM proteins have important functions in promoting host defense against virus infection; however, viruses have adapted to evade TRIM-mediated immune responses and can hijack TRIMs to ultimately increase virus pathogenesis. Only by understanding specific TRIM-virus interactions and by using more in vivo approaches can we learn how to harness TRIM function to develop therapeutic approaches to reduce virus pathogenesis.

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

“…Viral PAMPs and other viral components can be targeted by the host Ub system, including a subset of TRIMs, for ubiquitination-mediated degradation in most cases, and thus the IFN-I response is blocked at the very beginning to suppress viral replication, with some examples listed in Table 1 [ 54 , 58 ]. Of note, TRIM5α (also TRIM22) targets HIV1 Gag and plays a unique role in restricting HIV1 infection (and other retroviruses), implicating a potential clinical application [ 61 , 62 ].…”

“…The SPY-SPRY domain is critical for TRIM proteins' interaction with their substrates. Many TRIMs are inducible by IFN-Is, and play crucial roles in IFN-I-mediated innate immune regulation, with the involvement of ubiquitination and sumoylation in most cases [50,[52][53][54][55][56][57][58]. These TRIMs can target most if not all components of the PRR and Jak-STAT1 IFN-I pathways, including different ligands (PAMPs and DAMPs); the receptors such as TLRs, cGAS, and DDX41; the adaptors MyD88, TRIF, STING, and TRAF6 and -3; the kinases IKKs and TAK1; and the transcription factors IRF3 and -7 and NFκB (Table 1).…”

Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

“…Ubiquitination is removed from the substrate by deubiquitinating enzymes (DUBs), which allows for an “on/off” switch to regulate innate immune signaling (Reviewed in [ 1 , 10 ]). Moreover, noncovalent (also called ‘unanchored’) ubiquitination plays an emerging role in the regulation of innate immunity [ 11 , 12 ].…”

Toxoplasma gondii Type-I ROP18 Targeting Human E3 Ligase TRIM21 for Immune Escape

“…Tripartite motif (TRIM) proteins have emerged as an important family of E3 ligases that play a versatile role in innate immunity against infection ( Giraldo et al, 2020 ; Koepke et al, 2020 ; Lee et al, 2020 ; Wang and Hur, 2021 ). For instance, TRIM31 promotes the K63-linked polyubiquitination of mitochondrial antiviral signaling protein (MAVS) by inducing expression of interferons (IFNs) to against viral infection ( Liu et al, 2017 ).…”