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Review
. 2024 Jul 19;16(7):1161.
doi: 10.3390/v16071161.

Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins

Seeun Oh  1 , Michael A Mandell  1   2
Affiliations
Review

Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins

Seeun Oh et al. Viruses. .

Abstract

Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.

Keywords: MAVS; MDA5; RIG-I; STING; TBK1; TRIM; antiviral defense; autophagy; cGAS; inflammation; interferon; mitochondria; mitophagy; restriction factor; tripartite motif.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Regulation of TRIMs in innate immune signaling stimulated by viral PAMPs or mitochondrial DAMPs. When exposed to the cytosol, both viral PAMPs (e.g., viral DNA, dsRNA, etc.) and mitochondrial DAMPs can activate the same immune signal transduction pathways that are extensively regulated by TRIM proteins.
Figure 2
Figure 2
Regulation of MAVS signaling and stability by TRIM-mediated ubiquitination. MAVS contains 14 lysine residues distributed across its different domains, which include a single CARD domain, a proline-rich region (PRR), and a transmembrane domain (TM). Numbers in red indicate the target residues modified by TRIM-mediated ubiquitination. TRIM44 is a deubiquitinase that can stabilize MAVS by removing K48-linked polyubiquitin chains. TRIM7 is reported to induce K48-linked polyubiquitin chains, but the sites of TRIM7-mediated MAVS ubiquitination were not determined.
Figure 3
Figure 3
TRIM5-mediated mitophagy regulates immune activation. (Top), schematic of mitophagy pathway. Unwanted or damaged mitochondria and associated immunostimulatory molecules (e.g., mtDNA) or signaling factors (e.g., MAVS) are sequestered within an autophagosome and subsequently degraded following autophagosome/lysosome fusion. Elimination of mtDAMPs or signaling factors can prevent or attenuate mitochondria-based immune activation. (Middle), mechanism of TRIM5-mediated mitophagy. Mitochondrial damage activates TRIM5’s ubiquitin ligase activity. Active TRIM5 associates with TBK1 via shared interactions with Sequestosome-like receptors (SLRs, e.g., Optineurin, NDP52, TAX1BP1, p62, and NBR1). TRIM5 then ubiquitinates TBK1, allowing for the assembly of TRIM5-SLR-TBK1 complexes on damaged mitochondria in a feed-forward manner. TBK1 is concentrated in these complexes, enabling it to become activated by trans-autophosphorylation and carry out mitophagy functions. (Bottom), reported roles of TBK1 in mitophagy. TRIM5 promotes TBK1 activity in mitophagy. TBK1 can then phosphorylate SLRs, Beclin 1, and RAB7A. Phosphorylation of SLRs increases their ability to bind to ubiquitin chains on damaged mitochondria and increases the ability of SLRs to associate with other autophagy factors on mitochondria. Beclin 1 is a component of the class III phosphatidylinositol 3-kinase (PI3K) complex, and its phosphorylation at Ser15 enhances the complex’s activity to generate PI3P, a requirement for the recruitment of downstream autophagy factors to the autophagosome initiation site. RAB7A is essential for mitophagy. Its activation by TBK1 is important for the recruitment of the pro-mitophagy protein Pacer into Beclin 1 complexes, which takes the place of the autophagy-inhibitory Rubicon protein. RAB7A also recruits ATG9A vesicles to the autophagy initiation site in a manner requiring TBK1.
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