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Review
. 2020;7(4):101-114.
doi: 10.1007/s40588-020-00150-8. Epub 2020 Aug 8.

TRIM Proteins in Host Defense and Viral Pathogenesis

Maria I Giraldo  1 , Adam Hage  1 , Sarah van Tol  1 , Ricardo Rajsbaum  1   2
Affiliations
Review

TRIM Proteins in Host Defense and Viral Pathogenesis

Maria I Giraldo et al. Curr Clin Microbiol Rep. 2020.

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.

Keywords: E3 ubiquitin ligase; Immunity; Pathogenesis; TRIM6; TRIM7; Tripartite motif (TRIM); Type I interferons; Ubiquitin; Virus infection.

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Conflict of interest statement

Conflict of InterestThe authors declare that they have no conflict of interest. The Rajsbaum lab is supported by grants R01AI134907, R21AI126012, and R21AI132479 from the National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) and funds from UTMB Institute for Human Infections & Immunity (IHII). A.H. is supported by T32 AI007526 and S.v.T is supported by T32 AI060549 from NIH/NIAID.

Figures

Fig. 1
Fig. 1
The TRIM effect: the forked road of host fitness or susceptibility. The TRIM family of proteins influence how hosts respond to foreign organisms leading to beneficial (host survival) or detrimental (host pathology) outcomes. This duality is linked to whether a particular TRIM retains desirable functions (antiviral or pro-viral participation) and if the negative consequences accompanying TRIM involvement outweigh their positive contributions (failure to tolerate subsequent inflammatory responses)
Fig. 2
Fig. 2
Pro-viral and antiviral roles of TRIM6. a TRIM6 facilities the ubiquitination (white circles with Ub) of Ebola virus (EBOV) VP35 at lysine residue 309 (K309). This ubiquitination at K309 augments the EBOV VP35’s polymerase co-factor activity in the presence of TRIM6. b Upon virus infection, viral RNA in the cytoplasm triggers the activation of RIG-I-like receptors, including RIG-I and MDA-5, to trigger downstream type-I interferon (IFN-I) induction. TRIMs 6 and 25 both participate in the IFN-I pathway. TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains which act as a scaffold for IKKɛ oligomerization promoting its kinase activity and downstream functions in IFN-I induction and signaling, and TRIM6 regulates that expression of a vesicle-associated protein, VAMP8, which has been shown to promote JAK1 phosphorylation downstream of IFN-I signaling. TRIM25 facilities the covalent conjugation of K63-linked polyubiquitin to RIG-I to promote RIG-I’s activity. The viral antagonism (red arrows) of these TRIMs’ function has been described for EBOV VP35 and Nipah virus (NiV) accessory protein V (V) and matrix protein (M). In addition to the antagonism of TRIMs, these viral proteins also target additional steps of the IFN-I pathways, including NiV-V antagonism of MDA5 and STAT1 and EBOV antagonism of IKKɛ- and TBK1-mediated phosphorylation of IRF3
Fig. 3
Fig. 3
a A portion of released Zika virions possess ubiquitinated envelope proteins. Zika virus grown in both human and mosquito cells are ubiquitinated to varying degrees with human grown viruses having longer poly-Ub chains while mosquito-grown viruses retain shorter poly-Ub chains. b Envelope ubiquitination by TRIM7 enhances Zika virus entry in mammalian, but not mosquito, hosts. Ubiquitination of the Zika envelope protein at site K38 is made possible by the E3 ubiquitin ligase TRIM7 allowing for enhanced Zika tissue tropism where levels of TRIM7 are high (brain, uterus, and testis). c Ubiquitination of Zika envelope promotes binding to host receptors and enhances viral entry. The K63-poly-Ub chains of Zika envelope afford for stronger interactions with host receptors (#1), virus-endosome membrane fusion (#2), and higher replication titers (#3). Upon Zika infection, TRIM7 re-localizes to the Golgi and co-localizes with Zika envelope in distinct puncta where ubiquitination presumably occurs. Infectious Zika virions with ubiquitinated envelope can be neutralized with K63-regulate innate immune responses in both a positive and negative manner. TRIM7 promotes herpes virus infection by targeting STING for K48-poly-Ub and proteasome-mediated degradation (#5) while hindering norovirus replication (#6). Additionally, TRIM7 can also enhance TLR4 signaling in macrophages during LPS challenge (#7)
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