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CHIP promotes the activation of NF-κB signaling through enhancing the K63-linked ubiquitination of TAK1.

ABSTRACT: Transcriptional factor nuclear factor κB (NF-κB) can be activated by various intracellular or extracellular stimuli and its dysregulation leads to pathological conditions, such as neurodegenerative disorders, infection, and cancer. The carboxyl terminus of HSC70-interacting protein (CHIP), a pathogenic gene of spinocerebellar autosomal recessive 16 (SCAR16), plays an important roles in protein degradation, trafficking, and multiple signaling transductions. It has been reported that CHIP participates in the regulation of NF-κB signaling, and the mutant of CHIP (p.T246M) leads to the occurrence of SCAR16. However, the detailed mechanism of CHIP and CHIP (p.T246M) in the regulation of NF-κB signaling in neurological disorders remains unclear. Here, we found that CHIP promoted the activation of NF-κB signaling, while the knockdown had the opposite effect. Furthermore, CHIP interacted with TAK1 and targeted it for K63-linked ubiquitination. Finally, CHIP enhanced the interaction between TAK1 and NEMO. However, CHIP (p.T246M) couldn't upregulate NF-κB signaling, potentiate the ubiquitination of TAK1, and enhance the interactions. Taken together, our study demonstrated for the first time that CHIP positively regulates NF-κB signaling by targeting TAK1 and enhancing its K63-linked ubiquitination.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8448743 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Viruses have adopted diverse strategies to suppress antiviral responses. Hepatitis B virus (HBV), a virus that is prevalent worldwide, manipulates the host's innate immune system to evade scavenging. It is reported that the hepatitis B e antigen (HBeAg) can interfere with NF-?B activity, which then leads to high viral loads, while HBV with the G1896A mutation remains infectious without the production of HBeAg but can induce more severe proinflammatory response and liver damage. The aim of current work was to study the molecular mechanism by which HBeAg suppresses interleukin-1? (IL-1?)-stimulated NF-?B activity, which leads to the suppression of the innate immune responses to HBV infection. Our study revealed that HBeAg could interact with NEMO, a regulatory subunit associated with I?B kinase, which regulates the activation of NF-?B. HBeAg suppressed the IL-1?-induced tumor necrosis factor (TNF)-associated factor 6 (TRAF6)-dependent K63-linked ubiquitination of NEMO, thereby downregulating NF-?B activity and promoting virus replication. We further demonstrated the inhibitory effect of HBeAg on the NF-?B signaling pathway using primary human hepatocytes, HBV-infected HepG2-NTCP cells, and clinical liver samples. Our study reveals a molecular mechanism whereby HBeAg suppresses IL-1?-induced NF-?B activation by decreasing the TRAF6-dependent K63-linked ubiquitination of NEMO, which may thereby enhance HBV replication and promote a persistent infection.IMPORTANCE The role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-?B pathway are controversial. In this study, we showed that HBeAg could suppress both Toll-like receptor 2 (TLR2)- and IL-1?-induced activation of NF-?B in cells and clinical samples, and we further revealed novel molecular mechanisms. We found that HBeAg can associate with NEMO, the regulatory subunit for I?B kinase (IKK) that controls the NF-?B signaling pathway, and thereby inhibits TRAF6-mediated K63-linked ubiquitination of NEMO, resulting in downregulation of NF-?B activity and promotion of virus replication. In contrast, the HBeAg-negative HBV mutant can induce higher levels of NF-?B activity. These results are important for understanding the HBV-induced pathogenesis of chronic hepatitis and indicate that different clinical measures should be considered to treat HBeAg-positive and HBeAg-negative infections. Our findings represent a conceptual advance in HBV-related suppression of NF-?B signaling.

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CHIP promotes the activation of NF-κB signaling through enhancing the K63-linked ubiquitination of TAK1.

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