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Review
. 2024 Aug 12;16(8):1285.
doi: 10.3390/v16081285.

The Dual Role of TRIM7 in Viral Infections

Maria Gonzalez-Orozco  1 , Carlos A Rodriguez-Salazar  1   2 , Maria I Giraldo  1
Affiliations
Review

The Dual Role of TRIM7 in Viral Infections

Maria Gonzalez-Orozco et al. Viruses. .

Abstract

The E3 ubiquitin ligase TRIM7 is known to have dual roles during viral infections. Like other TRIM proteins, TRIM7 can regulate the IFN pathway via the regulation of the cytosolic receptors RIG-I or MDA-5, which promote the production of type I interferons (IFN-I) and antiviral immune responses. Alternatively, under certain infectious conditions, TRIM7 can negatively regulate IFN-I signaling, resulting in increased virus replication. A growing body of evidence has also shown that TRIM7 can, in some cases, ubiquitinate viral proteins to promote viral replication and pathogenesis, while in other cases it can promote degradation of viral proteins through the proteasome, reducing virus infection. TRIM7 can also regulate the host inflammatory response and modulate the production of inflammatory cytokines, which can lead to detrimental inflammation. TRIM7 can also protect the host during infection by reducing cellular apoptosis. Here, we discuss the multiple functions of TRIM7 during viral infections and its potential as a therapeutic target.

Keywords: TRIM7; antiviral response; ubiquitination; viral infections.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The pro- and anti-tumoral functions of TRIM7. (A) Depicts the predicted protein architecture encoded by the GNIP (TRIM7) gene in cartoon form. The numbers indicate the approximate demarcation of the different domains for (A.1) GNIP1, (A.2) GNIP2, (A.3) GNIP3, and (A.4) TRIM7 short form. (B.1) The c-Jun/AP-1 transcription factor is crucial for proliferation and apoptosis. MSK1 phosphorylates TRIM7 in response to direct activation by the Ras-Raf-MEK-ERK pathway. This modification stimulates TRIM7 and mediates Lys63-linked ubiquitination of RACO-1, leading to RACO-1 protein stabilization. Consequently, TRIM7 depletion reduces RACO-1 levels and RACO-1-dependent gene expression. (B.2) Modifying TRIM7 mRNA with N6-methyladenosine (m6A) through METTL3/14-YTHDF2 decreases its expression. This regulation enables TRIM7 to control the migration and invasiveness of osteosarcoma cells by ubiquitinating the breast cancer metastasis suppressor (BRMS1). (B.3) TRIM7 can regulate autophagy. Biochemically, GNIP1 binds to BECN1 and LC3B, inducing autophagy by promoting the formation of autophagic protein complexes. Additionally, TRIM7 promotes autophagy progression by mediating the K48-linked ubiquitination of 14-3-3ζ, a negative regulator of autophagy. (B.4) Ferroptosis is induced by the excessive accumulation of lipid hydroperoxides in the cellular membrane. GPX4 regulates lipid peroxidation using GSH to reduce lipid hydroperoxides (LOOH) to lipid alcohols (LOH), suppressing ferroptosis. GSH is oxidized to GSSG in this process. When SLC7A11 is ubiquitinated BY TRIM7, the system xc- is truncated, accumulating LOOH and subsequent ferroptosis, inhibiting gastric cancer progression. GR: glutathione reductase, GPX4: glutathione peroxidase 4, GSH: reduced glutathione, GSSG: oxidized glutathione (glutathione disulfide), LOOH: lipid hydroperoxide, LOH: lipid alcohol, EA: excessive accumulation. Black arrows indicate positive activation of the pathway, and red arrows indicate negative regulation of the pathway by promoting degradation of the protein. Figure was created with BioRender.com.
Figure 2
Figure 2
Proviral and antiviral roles of TRIM7. (A) During ZIKV infection, viral entry occurs after viral attachment and endocytosis that leads to clathrin-mediated endocytosis, followed by uncoating of the viral genome, and after viral genome replication, the viral polyprotein is generated; this leads to viral assembly in the ER where E protein is ubiquitinated in a K63 manner by TRIM7, the virus is then matured and is released from the cells. The ubiquitination of E protein mediated by TRIM7 enhances the binding of the virus with its receptor TIM-1, increasing viral replication in the brain and reproductive cells. (B) TRIM7 regulates innate immune receptors. Upon recognition of PAMPs, pattern recognition receptors such as endosomal Toll-like receptors (TLRs 3, 4, 7–9) and cytosolic RIG-I-like receptors initiate signaling pathways to induce the production of pro-inflammatory cytokines and interferons (IFNs), TRIM7 negatively regulates major cytosolic receptors RIG-I and MDA-5 by inducing K48-linked ubiquitination of the adaptor protein MAVs, leading to its degradation via the proteasome, thus inhibiting IFN-I production. Similarly, TRIM7 ubiquitinates the DNA receptor STING in a K48-linked manner, resulting in proteasomal degradation and reduced IFN-I production, facilitating increased replication of DNA viruses such as HSV-1. (C) TRIM7 also positively regulates the inflammatory response following TLR4 activation by LPS. TRIM7 expression is crucial for inducing the phosphorylation of ERK1/2, p38, JNK1/2, IKKα/β, and IRF3, leading to the activation of signaling pathways for the production of cytokines such as IL-6, TNF, and IFN-β in macrophages. PAMPs: pathogen-associated molecular patterns, TLRs: Toll-like receptors, MAVs: mitochondrial antiviral-signaling protein, STING: stimulator of interferon genes, LPS: lipopolysaccharide, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, IKK: IκB kinase, IRF: interferon regulatory factor, IL: interleukin, TNF: tumor necrosis factor. Black arrows indicate positive activation of the pathway, and red arrows indicate that TRIM7 promotes the degradation of the protein. Figure was created with BioRender.com.
Figure 3
Figure 3
The antiviral role of TRIM7 during enteroviruses replication. (A) TRIM7 recognizes and ubiquitinates the viral protein 2BC of coxsackievirus (CVB3), a precursor of the 2C protein, TRIM7 recognized the 2C portion of the protein, specifically the glutamine Q329 leading to its ubiquitination and degradation of the protein through proteasome reducing the CVB3 replication. After multiple passages, the pressure exerted by TRIM7 led to a mutation in the protein 2C on position T323, a change for an alanine to avoid the restriction mediated by TIRM7. (B) In norovirus infection, TRIM7 recognized the glutamine-end motif of the NTPAse/NS6 protein leading to ubiquitination and degradation of this one reducing virus replication. TRIM7 can also bind to the viral protease NS6 but not to the NS6-7 precursor protein. Through a mechanism not described yet, this interaction regulates viral replication; however, in a way to escape TRIM7 recognition, norovirus is able to induce a mutation in the position F182 avoiding the targeting by TRIM7 and allowing the virus to replicate. Black arrows indicate positive activation of the pathway, and red arrows indicate that TRIM7 promotes degradation of the protein, inhibitory red arrows indicate the inhibitory effect mediated by TRIM7-induced ubiquitination. Figure was created with BioRender.com.
Figure 4
Figure 4
TRIM7 during SARS-CoV-2 infection. SARS-CoV-2 is recognized by ACE-2 receptor; following entry and uncoating of its genetic material, it starts replication and transcription of the proteins, and the polyprotein is cleaved into 16 non-structural proteins (NSPs) and 4 structural proteins. Then the RNA is packaged, and the viral particle is assembled to generate a mature virus. Non-structural proteins (NSPs) of SARS-CoV-2 and the structural membrane (M) protein possess a glutamine-end motif recognized by TRIM7. Specifically, NSP5 and NSP8 interact with TRIM7, leading to K48-linked ubiquitination and subsequent degradation of these proteins, thereby enhancing IFN-I production and reducing virus replication. TRIM7’s interaction with the M protein results in ubiquitination at the lysine 14 residue, which restricts apoptosis induced by M. Additionally, TRIM7 negatively regulates caspase-6 activation, preventing the cleavage of the nucleocapsid (N) protein thereby restricting apoptosis. TRIM7 regulates the inflammatory response during SARS-CoV-2 infection by inducing the production of pro-inflammatory cytokines IL-6, IL-1β, and IL-1α and the chemokine CXCL1 leading to the recruitment of monocytes and neutrophils to the infected lungs to help promote clearance of apoptotic cells and tissue repair. Black arrows indicate positive activation of the pathway, red arrows indicate that TRIM7 promotes degradation of the protein, inhibitory red arrows indicate the inhibitory effect mediated by TRIM7-induced ubiquitination, and question marks indicate that the effect is not confirmed experimentally but is suggested by the literature or downstream signaling elements have not been dissected yet. Figure was created with BioRender.com.
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Grants and funding

This work was supported by the US National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) grant number R01AI134907 and the Building Interdisciplinary Research Careers in Women’s Health Program (BIRCWH) K12HD052023 awarded to M.I.G.

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