ArticleThe Journal of biological chemistry2015
Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-κB-inducing kinase (NIK) and suppresses NIK-induced liver injury.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- The NF-κB Signalling Pathway: Mechanisms, Consequences and Therapeutic Targets.Journal of cellular and molecular medicine · 2026Review
- Biliary NF-κB-Inducing Kinase Promotes Ductular Reaction, Inflammation, and Fibrosis and Impedes Liver Disease Resolution.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- CHIP/STUB1 suppresses the transcription and latent reactivation of HIV-1 via the TRAF6-NF-κB-HIV-LTR axis.PLoS pathogens · 2025Article
- Sec10 suppresses antiviral innate immune response by facilitating STUB1-mediated STAT1 degradation.PLoS pathogens · 2025Article
- The STUB1-TPIT axis regulates the secretion of adrenocorticotrophic hormone in cushing disease.Journal of translational medicine · 2025Article
- CHIP mediates glucagon action on hepatic glucose production via regulating Smad3 ubiquitination.Diabetes, obesity & metabolism · 2025Article
- HSP90 and the cancer transcriptome: a comprehensive review of inhibitors and mechanistic insights.International journal of clinical oncology · 2025Review
- The role of ubiquitination and deubiquitination in the pathogenesis of non-alcoholic fatty liver disease.Frontiers in immunology · 2025Review
- CHIP drives proteasomal degradation of NUR77 to alleviate oxidative stress and intrinsic apoptosis in cisplatin-induced nephropathy.Communications biology · 2024Article
- CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses.Antioxidants (Basel, Switzerland) · 2023Article
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation.Journal of experimental & clinical cancer research : CR · 2022Article
- The Therapeutic Potential of Targeting NIK in B Cell Malignancies.Frontiers in immunology · 2022Review
- Noncanonical NF-κB Signaling Pathway in Liver Diseases.Journal of clinical and translational hepatology · 2021Review
- BYHWD Alleviates Inflammatory Response by NIK-Mediated Repression of the Noncanonical NF-κB Pathway During ICH Recovery.Frontiers in pharmacology · 2021Article
- Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury.Frontiers in molecular biosciences · 2021Article
- Conserved and Unique Roles of Chaperone-Dependent E3 Ubiquitin Ligase CHIP in Plants.Frontiers in plant science · 2021Review
- Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?Cancers · 2020Review
- Hepatoprotective Effect of Apigenin Against Liver Injury via the Non-canonical NF-κB Pathway In Vivo and In Vitro.Inflammation · 2020Article
- Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study.Signal transduction and targeted therapy · 2020Review
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Ser/Thr kinase NIK (NF-κB-inducing kinase) mediates the activation of the noncanonical NF-κB2 pathway, and it plays an important role in regulating immune cell development and liver homeostasis. NIK levels are extremely low in quiescent cells due to ubiquitin/proteasome-mediated degradation, and cytokines stimulate NIK activation through increasing NIK stability; however, regulation of NIK stability is not fully understood. Here we identified CHIP (carboxyl terminus of HSC70-interacting protein) as a new negative regulator of NIK. CHIP contains three N-terminal tetratricopeptide repeats (TPRs), a middle dimerization domain, and a C-terminal U-box. The U-box domain contains ubiquitin E3 ligase activity that promotes ubiquitination of CHIP-bound partners. We observed that CHIP bound to NIK via its TPR domain. In both HEK293 and primary hepatocytes, overexpression of CHIP markedly decreased NIK levels at least in part through increasing ubiquitination and degradation of NIK. Accordingly, CHIP suppressed NIK-induced activation of the noncanonical NF-κB2 pathway. CHIP also bound to TRAF3, and CHIP and TRAF3 acted coordinately to efficiently promote NIK degradation. The TPR but not the U-box domain was required for CHIP to promote NIK degradation. In mice, hepatocyte-specific overexpression of NIK resulted in liver inflammation and injury, leading to death, and liver-specific expression of CHIP reversed the detrimental effects of hepatic NIK. Our data suggest that CHIP/TRAF3/NIK interactions recruit NIK to E3 ligase complexes for ubiquitination and degradation, thus maintaining NIK at low levels. Defects in CHIP regulation of NIK may result in aberrant NIK activation in the liver, contributing to live injury, inflammation, and disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.