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 Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling

2007 ◽  
Vol 204 (5) ◽  
pp. 1013-1024 ◽  
Author(s):  
Tatsukata Kawagoe ◽  
Shintaro Sato ◽  
Andreas Jung ◽  
Masahiro Yamamoto ◽  
Kosuke Matsui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Toll Like Receptor ◽  
Tcr Signaling ◽  
Mitogen Activated Protein

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

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.

The role of ubiquitin in neurotrophin receptor signalling and sorting

2006 ◽  
Vol 34 (5) ◽  
pp. 757-760 ◽  
Author(s):  
M.W. Wooten ◽  
T. Geetha
Keyword(s):  
Neurotrophin Receptor ◽  
Tumour Necrosis Factor Receptor ◽  
Receptor Kinase ◽  
Polyubiquitin Chains ◽  
Receptor Signalling ◽  
Kinase C ◽  
Ubiquitin Conjugating Enzyme ◽  
P75 Receptor ◽  
Necrosis Factor

NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62–TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.

Role of adapters in Toll-like receptor signalling

2003 ◽  
Vol 31 (3) ◽  
pp. 637-642 ◽  
Author(s):  
S. Akira ◽  
M. Yamamoto ◽  
K. Takeda
Keyword(s):  
Biological Effects ◽  
Interleukin 1 ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Receptor Signalling ◽  
Signalling Molecule ◽  
Repeat Domain

Toll-like receptors (TLRs) play a critical role in the detection of invading pathogens within the body and the subsequent immune response. Individual TLRs recognize distinct microbial components. The TLRs are a type 1 transmembrane receptor that possess an extracellular leucine-rich repeat domain and cytoplasmic domain homologous with that of the interleukin 1 receptor (IL-1R) family. Upon stimulation, TLR recruits the IL-1R-associated kinase (IRAK) via the adapter MyD88, ultimately leading to the activation of nuclear factor-κB. Cytokine production in response to all TLR ligands is completely abolished in MyD88-deficient cells, indicating that MyD88 is an essential signalling molecule shared among members of the IL-1R/Toll family. However, several novel adaptor molecules have recently been identified. Evidence is now accumulating showing that differential utilization of these adaptors may activate overlapping as well as distinct signalling pathways, and ultimately give rise to distinct biological effects exerted by individual TLR family members.

scholarly journals A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)

2003 ◽  
Vol 370 (1) ◽  
pp. 159-166 ◽  
Author(s):  
Ken YANAGISAWA ◽  
Kenji TAGO ◽  
Morisada HAYAKAWA ◽  
Motomichi OHKI ◽  
Hiroyuki IWAHANA ◽  
...  
Keyword(s):  
Splice Variant ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Acceptor Site ◽  
Nuclear Factor ◽  
Death Domain ◽  
Signalling Molecule ◽  
Novel Variant ◽  
Nf Kappab

Interleukin-1 (IL-1)-receptor-associated kinase (IRAK) is an indispensable signalling molecule for host-defence responses initiated by a variety of ligands that bind to members of the Toll/IL-1 receptor family. Here we report a novel splice variant of mouse IRAK-1, IRAK-1-S, which is generated by utilizing a new splicing acceptor site within exon 12. IRAK-1-S cDNA is shorter than the originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent frameshift causes a premature termination of translation after 23 amino acids, which are unique to the IRAK-1-S protein. To elucidate the physiological function of IRAK-1-S, we overexpressed it in 293T cells and studied the effects on the IL-1 signalling cascade. As it lacks the C-terminal region of IRAK-1-W that has been reported to contain the TRAF6 (tumour necrosis factor receptor-associated factor 6) binding domain, IRAK-1-S was unable to bind TRAF6 protein, which is a proposed downstream signalling molecule. However, IRAK-1-S overexpressed in 293T cells induced constitutive activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) independent of stimulation by IL-1, as did IRAK-1-W. To clarify the mechanism of NF-κB activation by IRAK-1-S in the absence of binding to TRAF6, we demonstrated that IRAK-1-S binds to IRAK-1-W through its death domain; the findings suggested that overexpressed IRAK-1-S may bind endogenous IRAK-1-W and activate TRAF6 through IRAK-1-W. These results also indicate that this novel variant may play roles in the activation of NF-κB and JNK by IL-1 and other ligands whose signal transduction is dependent on IRAK-1 under physiological conditions.

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