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Updated: May 13, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and
Han Fang1,2, Mengling Shi1,2, Cong Wang1,2
1State Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, Hubei 430072, China.
Abstract:
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. Pcsk9-/- mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus-host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a dual role in antiviral immunity. Intracellular PCSK9 stabilizes VISA, enhancing innate immune responses against RNA viruses, while secreted PCSK9 inhibits viral infection.
Area of Science:
- Immunology
- Virology
- Molecular Biology
- Metabolic Diseases
Background:
- Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate innate antiviral immunity via the mitochondrial adaptor protein VISA (also known as MAVS).
- VISA stability and activity are regulated by posttranslational modifications, including polyubiquitination mediated by E3 ubiquitin ligases like AIP4, leading to its degradation.
- The regulation of VISA polyubiquitination remains incompletely understood.
Purpose of the Study:
- To investigate the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in host responses to RNA viral infections.
- To elucidate the mechanisms by which PCSK9 modulates VISA stability and antiviral immunity.
Main Methods:
- Investigated the dual function of PCSK9 (extracellular and intracellular) in modulating host responses to Sendai virus (SeV) and vesicular stomatitis virus (VSV).
- Examined the effect of viral infection on PCSK9 translocation to mitochondria.
- Assessed the interaction of PCSK9 with VISA and its competition with AIP4.
- Analyzed the impact of PCSK9 overexpression and deficiency on VISA-mediated innate immune responses and viral replication.
- Studied the immune response in Pcsk9 knockout mice infected with VSV and influenza A virus.
Main Results:
- Secreted PCSK9 exhibited antiviral activity against SeV and VSV.
- Intracellular PCSK9 potentiated RIG-I-like receptor (RLR)-mediated interferon (IFN) induction by stabilizing VISA on mitochondria.
- Viral infection induced PCSK9 translocation to mitochondria, where it competed with AIP4, inhibiting VISA polyubiquitination and degradation.
- PCSK9 overexpression enhanced antiviral immunity, while PCSK9 deficiency led to increased viral replication and reduced type I IFNs and cytokine production.
- Pcsk9 mice showed increased sensitivity to VSV and influenza A virus infection.
Conclusions:
- PCSK9 plays a significant and previously unrecognized role in virus-host interactions.
- Intracellular PCSK9 acts as a crucial regulator of VISA stability, thereby enhancing the innate immune response against RNA viruses.
- These findings contribute to understanding the intricate mechanisms governing effective antiviral immunity.
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