title: Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-κB-inducing kinase (NIK) and suppresses NIK-induced liver injury.
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.
authors: From the National Beef Cattle Improvement Center, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China and the Departments of Molecular and Integrative Physiology and.
authors: Bijie
authors: B
authors: Jiang
authors: the Departments of Molecular and Integrative Physiology and.
authors: Hong
authors: H
authors: Shen
authors: the Departments of Molecular and Integrative Physiology and.
authors: Zheng
authors: Z
authors: Chen
authors: the Departments of Molecular and Integrative Physiology and.
authors: Lei
authors: L
authors: Yin
authors: From the National Beef Cattle Improvement Center, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China and zanlinsen@163.com.
authors: Linsen
authors: L
authors: Zan
authors: the Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622 ruily@umich.edu.
authors: Liangyou
authors: L
authors: Rui
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004789:Enzyme Activation; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000293:injuries*; D008297:Male; D051379:Mice; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D052003:NF-kappa B p52 Subunit; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse
keywords: Inflammation; Liver Injury; NF-kappa B (NF-KB); Protein Degradation; Ubiquitylation (Ubiquitination)