scholarly journals Two distinct signalling cascades target the NF-κB regulatory factor c-IAP1 for degradation

2009 ◽  
Vol 420 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Rebecca A. Csomos ◽  
Casey W. Wright ◽  
Stefanie Galbán ◽  
Karolyn A. Oetjen ◽  
Colin S. Duckett
Keyword(s):  
Large Cell ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Tumour Necrosis Factor Receptor ◽  
Physiological Mechanisms ◽  
Cellular Processes ◽  
Signalling Cascades ◽  
New Gene ◽  
Factor C ◽  
Necrosis Factor

c-IAP1 (cellular inhibitor of apoptosis 1) has recently emerged as a negative regulator of the non-canonical NF-κB (nuclear factor κB) signalling cascade. Whereas synthetic IAP inhibitors have been shown to trigger the autoubiquitination and degradation of c-IAP1, less is known about the physiological mechanisms by which c-IAP1 stability is regulated. In the present paper, we describe two distinct cellular processes that lead to the targeted loss of c-IAP1. Recruitment of a TRAF2 (tumour necrosis factor receptor-associated factor 2)–c-IAP1 complex to the cytoplasmic domain of the Hodgkin's/anaplastic large-cell lymphoma-associated receptor, CD30, leads to the targeting and degradation of the TRAF2–c-IAP1 heterodimer through a mechanism requiring the RING (really interesting new gene) domain of TRAF2, but not c-IAP1. In contrast, the induced autoubiquitination of c-IAP1 by IAP antagonists causes the selective loss of c-IAP1, but not TRAF2, thereby releasing TRAF2. Thus c-IAP1 can be targeted for degradation by two distinct processes, revealing the critical importance of this molecule as a regulator of numerous intracellular signalling cascades.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

scholarly journals Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion

2011 ◽  
Vol 32 (2) ◽  
pp. 105-112 ◽  
Author(s):  
Mark D. Turner ◽  
Anupama Chaudhry ◽  
Belinda Nedjai
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Cytokine Secretion ◽  
Mitogen Activated Protein Kinase ◽  
Tumour Necrosis Factor Receptor ◽  
Tnfrsf1a Gene ◽  
Mitogen Activated Protein ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Cytokines are secreted from macrophages and other cells of the immune system in response to pathogens. Additionally, in autoinflammatory diseases cytokine secretion occurs in the absence of pathogenic stimuli. In the case of TRAPS [TNFR (tumour necrosis factor receptor)-associated periodic syndrome], inflammatory episodes result from mutations in the TNFRSF1A gene that encodes TNFR1. This work remains controversial, however, with at least three distinct separate mechanisms of receptor dysfunction having been proposed. Central to these hypotheses are the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) families of transcriptional activators that are able to up-regulate expression of a number of genes, including pro-inflammatory cytokines. The present review examines each proposed mechanism of TNFR1 dysfunction, and addresses how these processes might ultimately impact upon cytokine secretion and disease pathophysiology.

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells

2014 ◽  
Vol 112 (09) ◽  
pp. 580-588 ◽  
Author(s):  
Sung Kyul Lee ◽  
Seung-Hee Yang ◽  
Il Kwon ◽  
Ok-Hee Lee ◽  
Ji Hoe Heo
Keyword(s):  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Necrosis Factor

SummaryTumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Structural basis for phosphorylation-triggered autophagic clearance of Salmonella

2013 ◽  
Vol 454 (3) ◽  
pp. 459-466 ◽  
Author(s):  
Vladimir V. Rogov ◽  
Hironori Suzuki ◽  
Evgenij Fiskin ◽  
Philipp Wild ◽  
Andreas Kniss ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Nuclear Factor Κb ◽  
Structural Basis ◽  
Side Chain ◽  
Tryptophan Residue ◽  
Tumour Necrosis Factor Receptor ◽  
Selective Autophagy ◽  
Phenylalanine Residue ◽  
Necrosis Factor ◽  
Micromolar Range

Selective autophagy is mediated by the interaction of autophagy modifiers and autophagy receptors that also bind to ubiquitinated cargo. Optineurin is an autophagy receptor that plays a role in the clearance of cytosolic Salmonella. The interaction between receptors and modifiers is often relatively weak, with typical values for the dissociation constant in the low micromolar range. The interaction of optineurin with autophagy modifiers is even weaker, but can be significantly enhanced through phosphorylation by the TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1}. In the present study we describe the NMR and crystal structures of the autophagy modifier LC3B (microtubule-associated protein light chain 3 beta) in complex with the LC3 interaction region of optineurin either phosphorylated or bearing phospho-mimicking mutations. The structures show that the negative charge induced by phosphorylation is recognized by the side chains of Arg11 and Lys51 in LC3B. Further mutational analysis suggests that the replacement of the canonical tryptophan residue side chain of autophagy receptors with the smaller phenylalanine side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serine residues directly N-terminally located to the phenylalanine residue, the affinity is increased to the level normally seen for receptor–modifier interactions. Phosphorylation, therefore, acts as a switch for optineurin-based selective autophagy.

Isolation and characterization of two novel A20-like proteins

2001 ◽  
Vol 357 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Paul C. EVANS ◽  
Ellen R. TAYLOR ◽  
John COADWELL ◽  
Karen HEYNINCK ◽  
Rudi BEYAERT ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Sequence Similarity ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Tumour Necrosis Factor Receptor ◽  
Isolation And Characterization ◽  
Important Negative Regulator ◽  
Inflammatory Processes ◽  
Cellular Zinc

The transcription factor nuclear factor κB (NF-κB) plays a pivotal role in inflammatory processes through induction of adhesion molecules and chemokines. The zinc finger molecule A20 is an important negative regulator of NF-κB. The mechanism utilized by A20 is not fully understood, but A20 has been shown to bind to tumour-necrosis-factor-receptor-associated factor (TRAF) molecules, which are necessary for pro-inflammatory cytokine signalling. We report two novel genes, Cezanne (cellular zinc finger anti-NF-kB) and TRABID (TRAF-bnding domain), with sequence similarity to A20. Co-immunoprecipitation studies indicated that TRAF6 was able to interact with both Cezanne and TRABID. In contrast, reporter gene experiments revealed a specific ability of Cezanne to down-regulate NF-κB. It is likely, therefore, that Cezanne participates in the regulation of inflammatory processes.

A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-κB1 p105 to p50: A potential for a tumor-suppressive PROTAC

2021 ◽  
Vol 118 (49) ◽  
pp. e2117254118
Author(s):  
Gilad Goldhirsh ◽  
Yelena Kravtsova-Ivantsiv ◽  
Gandhesiri Satish ◽  
Tamar Ziv ◽  
Ashraf Brik ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Nuclear Factor Κb ◽  
Free System ◽  
Von Hippel Lindau ◽  
Cellular Processes ◽  
Broad Array ◽  
New Gene ◽  
A Cell

Nuclear factor κB (NF-κB) is an important transcriptional regulator that is involved in numerous cellular processes, including cell proliferation, immune response, cell survival, and malignant transformation. It relies on the ubiquitin–proteasome system (UPS) for several of the steps in the concerted cascade of its activation. Previously, we showed that the ubiquitin (Ub) ligase KPC1 is involved in ubiquitination and limited proteasomal processing of the NF-κB1 p105 precursor to generate the p50 active subunit of the “canonical” heterodimeric transcription factor p50–p65. Overexpression of KPC1 with the generation of an excessive amount of p50 was shown to suppress tumors, an effect which is due to multiple mechanisms. Among them are suppression of expression of programmed cell death-ligand 1 (PD-L1), overexpression of a broad array of tumor suppressors, and secretion of cytokines which results in recruitment of suppressive immune cells into the tumor. Here, we show that the site of KPC1 to which p105 binds is exceptionally short and is made up of the seven amino acids WILVRLW. Attachment of this short stretch to a small residual part (∼20%) of the ligase that also contains the essential Really Interesting New Gene (RING)-finger domain was sufficient to bind p105, conjugate to it Ub, and suppress tumor growth in an animal model. Fusion of the seven amino acids to a Von Hippel–Lindau protein (pVHL)-binding ligand (which serves as a “universal” ligase for many proteolysis-targeting chimeras; PROTACs) resulted in a compound that stimulated conjugation of Ub to p105 in a cell-free system and its processing to p50 in cells and restricted cell growth.

Structure of the A20 OTU domain and mechanistic insights into deubiquitination

2007 ◽  
Vol 409 (1) ◽  
pp. 77-85 ◽  
Author(s):  
David Komander ◽  
David Barford
Keyword(s):  
Biochemical Analysis ◽  
Nuclear Factor Κb ◽  
Catalytic Triad ◽  
Ovarian Tumour ◽  
Tumour Necrosis Factor Receptor ◽  
Catalytic Core ◽  
Interacting Protein ◽  
Kinase Activation ◽  
Necrosis Factor

The NF-κB (nuclear factor κB) regulator A20 antagonises IKK [IκB (inhibitor of κB) kinase] activation by modulating Lys63-linked polyubiquitination of cytokine-receptor-associated factors including TRAF2/6 (tumour-necrosis-factor-receptor-associated factor 2/6) and RIP1 (receptor-interacting protein 1). In the present paper we describe the crystal structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20, which differs from other deubiquitinases but shares the minimal catalytic core with otubain-2. Analysis of conserved surface regions allows prediction of ubiquitin-binding sites for the proximal and distal ubiquitin molecules. Structural and biochemical analysis suggests a novel architecture of the catalytic triad, which might be present in a subset of OTU domains including Cezanne and TRABID (TRAF-binding domain). Biochemical analysis shows a preference of the isolated A20 OTU domain for Lys48-linked tetraubiquitin in vitro suggesting that additional specificity factors might be required for the physiological function of A20 in cells.

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