Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling

Kollewe, Christian; Mackensen, Anne-Christin; Neumann, Detlef; Knop, Johannes; Cao, Ping; Li, Shyun; Wesche, Holger; Martin, Michael U.

doi:10.1074/jbc.m309251200

Cited by 218 publications

(242 citation statements)

References 40 publications

Supporting

Mentioning

223

Contrasting

Order By: Relevance

“…The signals responsible for this partial response are still unknown. One possibility may lie in the kinase activity of IRAK-1 (6,31). A small fraction of IRAK-1 molecules may be active at the receptor complex, or they may function in the cytosol in response to processed downstream signals.…”

Section: Discussionmentioning

confidence: 99%

“…The Role of IRAK-4 Kinase Activity on IL-1 Signaling Output-If IRAK-4 can function as a kinase and activate downstream substrates such as IRAK-1 (23,31), it is possible that the kinase activity of IRAK-4 plays a role in IL-1 signal transduction. Indeed, transient overexpression of wild type IRAK-4, but not kinase-inactive IRAK-4, in three independent IRAK-4-deficient cell lines was sufficient to rescue the IL-1-induced response as measured by NF-B-dependent reporter assays (one representative experiment is shown in Fig.…”

Section: Irak-4 Is Recruited To the Il-1rmentioning

confidence: 99%

See 1 more Smart Citation

The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling

Lye

Mirtsos

Suzuki

et al. 2004

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

Interleukin 1 receptor (IL-1R)-associated kinase-4 (IRAK-4) is required for various responses induced byIL-1R and Toll-like receptor signals. However, the molecular mechanism of IRAK-4 signaling and the role of its kinase activity have remained elusive. In this report, we demonstrate that IRAK-4 is recruited to the IL-1R complex upon IL-1 stimulation and is required for the recruitment of IRAK-1 and its subsequent activation/degradation. By reconstituting IRAK-4-deficient cells with wild type or kinase-inactive IRAK-4, we show that the kinase activity of IRAK-4 is required for the optimal transduction of IL-1-induced signals, including the activation of IRAK-1, NF-B, and JNK, and the maximal induction of inflammatory cytokines. Interestingly, we also discover that the IRAK-4 kinase-inactive mutant is still capable of mediating some signals. These results suggest that IRAK-4 is an integral part of the IL-1R signaling cascade and is capable of transmitting signals both dependent on and independent of its kinase activity.Toll-like receptors (TLRs) 1 are critical for receiving signals from molecular patterns associated with microbial pathogens to initiate innate immune responses (1-3). Interleukin 1 receptor (IL-1R) on the other hand is important for amplifying inflammatory responses triggered by microbial pathogens (4). Interestingly, signal transduction pathways mediated by the IL-1R and TLRs are very similar (5, 6). One common signaling pathway is initiated by the recruitment of the adaptor protein MyD88 to individual receptors upon ligand binding (7). MyD88 in turn is capable of recruiting IL-1 receptor-associated kinase (IRAK, also called IRAK-1) to the receptor complex (8). Upon activation and modification, IRAK-1 dissociates from the receptor complex and associates with tumor necrosis factor receptorassociated factor 6 (TRAF6) to trigger downstream signaling pathways (9 -12), including the activation of NF-B and various stress kinases such as c-Jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK).The apparently simple cascade of MyD883 IRAK3 TRAF6 became slightly more complex recently with a number of interesting discoveries. Starting from the top of the signaling cascade, three MyD88-like adaptor proteins, Mal (TIRAP), TRIF (TICAM-1), and TRAM (TICAM-2), were reported to play a role in mediating TLR signals (13). Although MyD88 is important in mediating signals for most TLRs and IL-1R (7), Mal helps transmit MyD88-dependent signals induced by TLR2 and TLR4 (14,15). TRIF is critical in mediating TLR3 and TLR4 signals, particularly interferon-responsive pathways (through IRF-3) that are 17), and TRAM associates with TLR4 specifically to signal along a TRIF-dependent pathway (18 -20).Studies of IL-1R/TLR signals at the level of IRAKs have also made important progress over the past two years. There are a total of four IRAK family members: IRAK-1, IRAK-2, IRAK-M, and IRAK-4 (10, 21-23). As deletion of the prototypical member IRAK-1 in mice reveals a partial defect in IL-1R/TLR signalin...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Irak-4 Is Recruited To the Il-1rmentioning

confidence: 99%

The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling

Lye

Mirtsos

Suzuki

et al. 2004

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

show abstract

“…IRAK-4 becomes activated by intramolecular autophosphorylation of three residues (Thr342, Thr345 and Ser346) within its activation loop, which is required for optimal kinase activity of IRAK-4 [28]. Activation of IRAK-4 leads to phosphorylation of IRAK-1 on Thr209 and Thr387 in its activation loop, leading to full kinase activity [23,29]. Subsequently, IRAK-1 becomes hyperphosphorylated in its ProST region, probably via autophosphorylation, resulting in its dissociation from MyD88 and Tollip, but not from the downstream signaling molecule TRAF6 [21,23].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

“…Activation of IRAK-4 leads to phosphorylation of IRAK-1 on Thr209 and Thr387 in its activation loop, leading to full kinase activity [23,29]. Subsequently, IRAK-1 becomes hyperphosphorylated in its ProST region, probably via autophosphorylation, resulting in its dissociation from MyD88 and Tollip, but not from the downstream signaling molecule TRAF6 [21,23]. However, the kinase activity of IRAK-1 is dispensable for IL-1 signaling towards NFkB, as complementation of cells deficient in IRAK-1 with a kinase death mutant can restore IL-1-induced NF-kB activation [29].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

398

297

View full text Add to dashboard Cite

Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

show abstract

“…MyD88 also contains a death domain that facilitates the subsequent recruitment of death-domain-containing IRAK1 and IRAK4 to the receptor complex [2] where IRAK1 is phosphorylated and activated by IRAK4 [5][6][7]. This is followed by intensive autophosphorylation of IRAK1 [5,6], its interaction with TRAF6 and subsequent dissociation of IRAK1 and TRAF6 as binding partners from the receptor complex [8][9][10]. TRAF6 then interacts with TIFA (TRAF-interacting protein with a FHA domain), which promotes oligomerization and ubiquitylation (Box 1) of the former [11].…”

Section: The Importance Of Pellino Proteins For Tlr Signallingmentioning

confidence: 99%

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Moynagh

2009

Trends in Immunology

133

102

View full text Add to dashboard Cite

Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling

Cited by 218 publications

References 40 publications

The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling

The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Contact Info

Product

Resources

About