Viral infection or TLR3 engagement causes activation of the transcription factors IRF-3 and NF-jB, which collaborate to induce transcription of type I IFN genes. IKKe and TBK1 are two IKK-related kinases critically involved in virus-and TLR3-triggered activation of IRF-3. We identified a protein termed SIKE (for Suppressor of IKKe) that interacts with IKKe and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKKe or TBK1 with TRIF, RIG-I and IRF-3, components in virus-and TLR3-triggered IRF-3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-jB activation pathway. Consistently, overexpression of SIKE inhibited virus-and TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-jB activation. Knockdown of SIKE potentiated virus-and TLR3-triggered ISRE but not NF-jB activation. Moreover, overexpression of SIKE inhibited IKKe-and TBK1-mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKKe and TBK1 and plays an inhibitory role in virus-and TLR3-triggered IRF-3 but not NF-jB activation pathways.
The transcription factor NFB plays important roles in immune regulation, inflammatory responses, and anti-apoptosis. Activation of NFB requires the activity of IB kinase, a kinase complex that contains two catalytic subunits, IKK␣ and IKK, and a non-enzymatic regulatory subunit, IKK␥. To understand how NFB activation is regulated at the IKK␥ level, we searched for IKK␥-interacting proteins by the yeast two-hybrid system. This search identified ZNF216, a zinc finger protein with unknown biological functions. ZNF216 contains an A20-like zinc finger domain (ZnF-A20) at its N terminus and an AN1-like domain (ZnF-AN1) at its C terminus. Similar to A20, ZNF216 interacted with IKK␥, RIP, and TRAF6 in co-immunoprecipitation experiments. Domain mapping experiments indicated that the ZnF-A20 domain was responsible for interacting with IKK␥ and RIP, whereas the ZnF-AN1 domain interacted with TRAF6. ZNF216 inhibited NFB activation triggered by overexpression of RIP and TRAF6 but not of p65. ZNF216 also inhibited tumor necrosis factor (TNF)-, interleukin-1-, and Tolllike receptor 4-induced NFB activation in a dose-dependent manner. The ZnF-A20 domain was essential for ZNF216-mediated inhibition of NFB activation. The ZnF-A20 and ZnF-AN1 domains of ZNF216 could interact with each other, whereas ZNF216 could form homo-oligomers or hetero-oligomers with A20. Unlike A20, which inhibits TNF-induced apoptosis, overexpression of ZNF216 sensitized cells to TNF-induced apoptosis. Our findings suggest that ZNF216 and A20 have redundant and distinct roles in regulating NFB activation and apoptosis.Nuclear factor B (NFB) 1 proteins are inducible transcription factors involved in a broad range of physiological and pathological processes (1-4). For example, NFB plays critical roles in immune regulation and inflammation through induction of a large set of downstream genes, including cytokines, chemokines, adhesion molecules, and effectors (1-4). Recent studies suggest that NFB also is critically involved in the regulation of cell death and survival through the transcriptional activation of genes important for anti-apoptosis and cell proliferation, such as Casper/c-FLIP, c-IAPs, TRAF1, TRAF2, Bfl-1/A1, Bcl-Xl, Fas ligand, c-myc, and cyclin D1 (1-4).NFB contains five members in mammals, Rel (c-Rel), RelA (p65), RelB, NFB1 (p50 and its precursor p105), and NFB2 (p52 and its precursor p100) (1-4). The major cellular form of NFB is a heterodimer consisting of the DNA binding subunit p50 and the transactivator p65. Normally, NFB is retained in the cytoplasm through association with its inhibitor IB. Upon stimulation by various NFB activating signals, IB is phosphorylated and degraded through a ubiquitin-dependent process. This process frees NFB, which is then translocated into the nucleus to activate transcription of downstream genes (1-4).Phosphorylation of IB is mediated by a kinase complex, called IB kinase (IKK) (5-10). IKK contains two catalytic subunits, IKK␣ (IKK1) and IKK (IKK2), and a non-enzymatic regulatory subunit IKK␥ (NEMO) (5-11...
We report here the identification of GIDE, a mitochondrially located E3 ubiquitin ligase. GIDE contains a C-terminal Ring finger domain, which is mostly conserved with those of the IAP family members, and which is required for its E3 ligase activity. Overexpression of GIDE induces apoptosis via a pathway involving activation of caspases since the caspase inhibitors, XIAP and an inactive mutant of caspase-9 block GIDE-induced apoptosis. GIDE also activates JNK, and blockade of JNK activation inhibits GIDE-induced release of cytochrome c and Smac and apoptosis, suggesting that JNK activation precedes release of cytochrome c and Smac and is required for GIDE-induced apoptosis. These proapoptotic properties of GIDE require its E3 ligase activity. When somewhat over or underexpressed, GIDE slows or hastens cell growth respectively. These pro-apoptotic or growth rate effects of GIDE may account for its absence from tumor cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.