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2024

The latest research by Guo Jianping/Cheng Chao/Bo Lang of Sun Yat-sen University confirms that palmitic acid can suppress virus infection by activating innate immunity!

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Innate immunity is the primary defense against viral and microbial infections. The exact effect of cellular metabolites, particularly fatty acids, on antiviral innate immunity remains largely elusive.

On September 9, 2024, Sun Yat-sen University Guo Jianping, Cheng Chao and Bo Lang jointly communicatedMolecular Cell（IF=14.5）Published online entitled“Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity”The research paper,The study showedTargeting APT2 improves MAVS palmitoylation and antiviral innate immunity.

Here, palmitic acid (PA) has been identified as a key regulator of antiviral infection in human cells by screening a metabolite library. Mechanically, PA induces palmitoylation, aggregation and subsequent activation of the mitochondrial antiviral signaling protein (MAVS), thereby enhancing the innate immune response.Palmitoyltransferase ZDHHC24 catalyzes the palmitoylation of MAVS, thereby promoting the TBK1-IRF3 interferon (IFN) pathway, especially under conditions of PA stimulation or high-fat diet fed mouse models, leading to antiviral immune responses.In addition, APT2 de-palmitoylated MAVS, thereby inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infection.These findings highlight the critical role of PA in modulating antiviral innate immunity through MAVS palmitoylation and provide strategies to increase PA intake or target APT2 against viral infections.

Innate immunity is the first line of defense against viral and microbial infections. Among them, pattern recognition receptors (PRRs) and cytosolic retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) play a crucial role in host defense and survival, mainly RNA virus infections. Notably, MDA5 and RIG-I are key RLRs that recognize viral double-stranded RNA (dsRNA) and trigger immune signaling through the adaptor protein mitochondrial antiviral signaling protein (MAVS), leading to the activation of the TANK-binding kinase 1/nuclear factor kappa B kinase subunit epsilon inhibitor (TBK1/IKBKE) kinase, interferon regulatory factor 3/7 (IRF3/7) pathway, this is followed by transcriptional induction of type I interferons (IFNs) and inflammatory cytokines type I IFNs.

In turn, it promotes the expression of IFNs-stimulated genes (ISGs) and enhances host resistance to viral and microbial infections. MAVS is a central receptor in this process and undergoes various post-translational modifications, including phosphorylation, ubiquitination, and palmitoylation, all of which regulate the expression of ISGs and contribute to anti-infection effects.Therefore, exploring upstream regulators of MAVS will provide alternative strategies to combat viral infections, including influenza, coronavirus, hepatitis C virus, etc.

Metabolic alterations, particularly palmitic acid (PA), a major component of palm oil and animal fats, play a key role in inflammation, immunity and tumorigenesis. The involvement of PA in the palmitoylation of various proteins is well documented.For example, palmitoylation of Toll-like receptor 2 (TLR2) can effectively activate the nuclear factor kappa B (NF-κB) signaling pathway, palmitoylation of MYD88 can promote TLR-induced inflammation, and palmitoylation of NOD1/2 can enhance its response to peptidoglycan. In addition, fatty acid-and ZDHHC19-mediated signal transducer and activator of transcription 3 (STAT3) palmitoylation can modulate inflammation and cancer. Recent evidence also highlights the importance of palmitoylation in the cyclic GMP-AMP synthetase (cGAS)-interferon gene stimulator (STING) anti-DNA virus pathway, in which ZDHHC1 and ZDHHC11 are positive regulators.

This study demonstrates that PA-and ZDHHC24-mediated palmitoylation of MAVS promotes MAVS aggregation and mitochondrial localization, thereby activating RLR-mediated innate immunity against RNA virus infection, which is counteracted by APT2. This study reveals the regulatory mechanism by which MAVS promotes PA-or high-fat diet-induced innate immune responses and suggests that targeting APT2 is a potential strategy to combat viral infection.

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