NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway.
The transcription factor NF-kappaB regulates genes involved in inflammatory and immune responses, tumorigenesis, and apoptosis. In contrast to the pleiotropic stimuli that lead to its positive regulation, the known signaling mechanisms that underlie the negative regulation of NF-kappaB are very few. Recent studies have identified the tumor suppressor CYLD, loss of which causes a benign human syndrome called cylindromatosis, as a key negative regulator for NF-kappaB signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (NF-kappaB essential modulator, also known as IkappaB kinase gamma). However, how CYLD is regulated remains unknown. The present study revealed a novel autoregulatory feedback pathway through which activation of NF-kappaB by TNF-alpha and bacterium nontypeable Haemophilus influenzae (NTHi) induces CYLD that in turn leads to the negative regulation of NF-kappaB signaling. In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi. These findings provide novel insights into the autoregulation of NF-kappaB activation.
Jono
Hirofumi
H
Gonda Department of Cell & Molecular Biology, House Ear Institute, and Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057, USA.
Lim
Jae Hyang
JH
Chen
Lin-Feng
LF
Xu
Haidong
H
Trompouki
Eirini
E
Pan
Zhixing K
ZK
Mosialos
George
G
Li
Jian-Dong
JD
D000818:Animals; D015153:Blotting, Western; D000074749:Deubiquitinating Enzyme CYLD; D005786:Gene Expression Regulation; D006193:Haemophilus influenzae / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism
D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD