Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-α-induced JNK1 activation

The proinflammatory cytokine TNF-α 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-α-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-α-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-α-induced TRAF2 K63-linked polyubiquitination. Neither JNK1 activation by IL-1β or UV nor TNF-α-induced activation of p38, ERK, or IκB kinase complex is affected by the loss of Miz1. The TNF-α-induced cell death also is accelerated in Miz1^-/- MEFs. Upon TNF-α 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-α-induced JNK1 activation and cell death.