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.

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 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.

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1740-1742 ◽  
Author(s):  
Ingrid Pollet ◽  
Christy J. Opina ◽  
Carla Zimmerman ◽  
Kevin G. Leong ◽  
Fred Wong ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Bacterial Lipopolysaccharide ◽  
Intracellular Signaling Pathway ◽  
Necrosis Factor

AbstractThe intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor κB (NF-κB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-κB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)–induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.

scholarly journals Tumour necrosis factor receptor-associated factors: interacting protein with forkhead-associated domain inhibition decreases inflammatory cell infiltration and cardiac remodelling after acute myocardial infarction

2020 ◽  
Vol 31 (1) ◽  
pp. 85-92 ◽  
Author(s):  
Yicheng Jiang ◽  
Xue Li ◽  
Hai Xu ◽  
Yang Gu ◽  
Feiya Shi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mouse Model ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cardiac Remodelling ◽  
Tumour Necrosis Factor Receptor ◽  
Tumour Necrosis Factor Α ◽  
Interacting Protein ◽  
Factor Α ◽  
Necrosis Factor

Abstract OBJECTIVES Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Post-AMI cardiac remodelling is closely related to the prognosis of AMI. The excess inflammatory responses could promote cardiac remodelling. Tumour necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) has been identified as a nuclear factor (NF)-κB activator, which plays a key role in the activation of the NF-κB signalling pathway. The goal of this research was to investigate the expression and the underlying mechanism of TIFA in an AMI mouse model. METHODS The AMI mouse model was induced by ligation of the left coronary artery. TIFA and NF-κB knockdown were established by lentivirus transduction. The expression levels of associated proteins were analysed by a western blot or an enzyme-linked immunosorbent assay. Histological characteristics were evaluated by haematoxylin–eosin staining. RESULTS The TIFA level was elevated in our AMI mouse model. The production of interleukin-1β and tumour necrosis factor-α increased markedly in the mice with AMI. TIFA knockdown inhibited the infiltration of inflammatory cells, production of pro-inflammatory mediators (interleukin-1β and tumour necrosis factor-α), NF-κB activation and cardiac remodelling (matrix metallopeptidase 9) post-AMI. In addition, NF-κB knockdown could also alleviate cardiac remodelling after AMI. CONCLUSIONS The preceding results indicated that TIFA inhibition could ameliorate cardiac remodelling after AMI partly through inactivation of NF-κB. This study provides insights into further research of cardiac remodelling and AMI from bench to clinic.

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