Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-alpha-induced JNK1 activation.
The proinflammatory cytokine TNF-alpha exerts its pleiotropic functions through activation of multiple downstream effectors, including JNK1. Yet, the underlying regulatory mechanism is incompletely understood. Here, we report that the transcription factor Myc-interacting zinc-finger protein 1 (Miz1) selectively suppresses TNF-alpha-induced JNK1 activation and cell death independently of its transcription activity. Proteomics analysis and yeast two-hybrid screening reveal that Miz1 is a JNK-associated protein. The TNF-alpha-induced activation of JNK1 is augmented in Miz1-deficient mouse embryonic fibroblasts (Miz1(-/-) MEFs), but the augmentation is abrogated by reintroduction of Miz1 or its transcription-deficient mutant. The regulation by Miz1 is highly specific, because it regulates TNF-alpha-induced TRAF2 K63-linked polyubiquitination. Neither JNK1 activation by IL-1beta or UV nor TNF-alpha-induced activation of p38, ERK, or IkappaB kinase complex is affected by the loss of Miz1. The TNF-alpha-induced cell death also is accelerated in Miz1(-/-) MEFs. Upon TNF-alpha stimulation, Miz1 is degraded rapidly by the proteasome, relieving its suppression on JNK1 activation. Thus, our results show that in addition to being a transcription factor Miz1 acts as a signal- and pathway-specific modulator or regulator that specifically regulates TNF-alpha-induced JNK1 activation and cell death.
Liu
Jing
J
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA. jing@northwestern.edu
Zhao
Yingming
Y
Eilers
Martin
M
Lin
Anning
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; C499176:T2bp protein, mouse; D014409:Tumor Necrosis Factor-alpha; C107961:ZBTB17 protein, human; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex