The role of TBK1 and IKKϵ in the expression and activation of Pellino 1

Smith, Hilary A.; Liu, Xin Yu; Dai, Liang; Goh, Eddy T. H.; Chan, Aye-Thu; Xi, Jiajia; Seh, Cheah-Chen; Qureshi, Insaf Ahmed; Lescar, Julien; Ruedl, Christiane; Gourlay, Robert; Morton, Simon; Hough, Joanne; McIver, Edward G.; Cohen, Philip; Cheung, Pierina

doi:10.1042/bj20101421

Cited by 63 publications

(72 citation statements)

References 43 publications

(63 reference statements)

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“…Fourth, the TGF-β1 anti-inflammatory activity mediated by degradation of MyD88 by the Smad6-Smurf pathway is likely to be effective in other MyD88-dependent TLR signalling pathways, not only the TLR4 pathway. However, our finding that the TLR3 pathway is inhibited through a mechanism mediated by TGF-β1-induced Smad6, which is not the Smad6-Smurf pathway, is inconsistent with results by Naiki et al 3 Interestingly, a recent report 41 suggests that TGF-β1 may inhibit MyD88-independent TLR3 signalling. Pellino-1 was identified as a binding partner of IKKε, and IKKε/TBK1 activated Pellino-1 in response to TLR3 and TLR4 agonists 41 .…”

Section: Discussioncontrasting

confidence: 99%

“…However, our finding that the TLR3 pathway is inhibited through a mechanism mediated by TGF-β1-induced Smad6, which is not the Smad6-Smurf pathway, is inconsistent with results by Naiki et al 3 Interestingly, a recent report 41 suggests that TGF-β1 may inhibit MyD88-independent TLR3 signalling. Pellino-1 was identified as a binding partner of IKKε, and IKKε/TBK1 activated Pellino-1 in response to TLR3 and TLR4 agonists 41 . The IKKε/TBK1 complex, which is downstream of the adaptor TRIF in TLR3 signalling, acts as protein kinases that activate the IRF3 transcription factor, stimulating expression of the IFNB1 gene 17,42 .…”

Section: Discussioncontrasting

confidence: 99%

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Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

et al. 2011

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Transforming growth factor-β (TGF-β) is a potent anti-inflammatory cytokine that regulates interleukin-1 receptor and Toll-like receptor (TLR) signalling. Here we show a novel mechanism where TGF-β1-induced K48-linked polyubiquitination and degradation of the adaptor myD88 protein is dependent on the smad6 protein, but not smad7, and mediated by recruitment of the smad ubiquitin regulator factor proteins, smurf1 and smurf2, which have E3-ubiquitin ligase activity. smurf1 interaction with myD88 appears to be mediated by smad6, and smurf2 interaction by smurf1. Knockdown of endogenous smurf1 or smurf2 by RnA interference significantly suppresses the anti-inflammatory effects of TGF-β1 by preventing lipopolysaccharide-induced nF-κB nuclear translocation, resulting in de-suppression of proinflammatory gene expression. similar effects are observed on the lipoteichoic-acid-induced TLR2 pathway, which is also myD88-dependent, but not the myD88-independent TLR3 pathway. Thus, our results suggest that myD88 degradation driven by the smad6-smurf pathway is a novel mechanism for TGF-β1-mediated negative regulation of myD88-dependent pro-inflammatory signalling.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

et al. 2011

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“…They contain a phosphorylated threonine-binding amino-terminal forkhead-associated (FHA) domain and a carboxy-terminal RING-like domain that facilitate the recruitment and K63-linked polyubiquitination, respectively, of kinases of the IRAK family, which are signaling intermediates in TLR pathways [28][29][30][31] . Pellino proteins undergo 9 2 8 VOLUME 14 NUMBER 9 SEPTEMBER 2013 nature immunology A r t i c l e s phosphorylation that regulates their E3 ligase activity [31][32][33][34][35] . Pellino1 is a key mediator of NF-κB activation in the TLR3 and TLR4 signaling pathways 36 and is a negative regulator of T cell activation 37,38 .…”

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confidence: 99%

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

et al. 2013

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The innate immune system is equipped with pattern-recognition receptors that recognize pathogen-associated molecular patterns 1 . Pattern-recognition receptors include transmembrane Toll-like receptors (TLRs) and cytosolic Nod-like receptors 2 . Nod1 and Nod2 recognize structures in bacterial peptidoglycan 3 . Loss-of-function mutants of Nod2 are associated with Crohn's disease 4-6 , whereas gain-offunction mutants result in predisposition to the development of earlyonset sarcoidosis and Blau syndrome 7,8 . Nod2 responds to muramyl dipeptide (MDP), a derivative of peptidoglycan 9,10 . Nod2 consists of two amino-terminal caspase-recruitment domains (CARDs), a central self-oligomerization NACHT region and multiple carboxyterminal leucine-rich repeats 11 . Engagement of the leucine-rich repeats by MDP promotes a conformational change that exposes the NACHT domain, which allows self-oligomerization of Nod2 and the binding of its CARDs to the CARD-containing kinase RIP2 (refs. 12,13). RIP2 interacts with the kinase TAK1, which leads to activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs) and induction of the expression of proinflammatory cytokines [14][15][16][17][18] . Ubiquitination of RIP2 is critical for Nod2 signaling pathways 15,16 .The attachment of polyubiquitin chains to RIP2 serves to recruit TAK1 via the adaptors TAB2 and TAB3 (ref. 19), and that facilitates TAK1-induced phosphorylation and activation of IκB kinases (IKKs) that induce phosphorylation of inhibitory IκB proteins 20 . Phosphorylated IκB proteins undergo proteasome-mediated degradation 21 that allows NF-κB to translocate to the nucleus and induce proinflammatory gene expression 22 . Studies have investigated the enzymes responsible for catalyzing the ubiquitination of RIP2. The Ubc13-Uev1a dimer acts as the E2 conjugating enzyme in the Lys63 (K63)-linked polyubiquitination of RIP2 (refs. 15,16), but the identity of the E3 ubiquitin ligase(s) that directly ubiquitinate(s) RIP2 to mediate Nod2-induced activation of NF-κB remains unclear. TRAF6 has been proposed as the main E3 ligase for RIP2 (ref. 15), but the ubiquitination of RIP2 is intact in TRAF6-deficient cells 16 and knockdown of TRAF6 does not affect RIP2-mediated activation of NF-κB 9,14 . Three members of the 'IAP' family of E3 ubiquitin ligases (XIAP, cIAP1 and cIAP2) have been proposed to regulate RIP2 ubiquitination 23,24 . Although the conclusions of the last two studies differ about the functional importance of cIAP1 and cIAP2 in mediating Nod2-induced ubiquitination of RIP2, one demonstrated that XIAP promotes the ubiquitination of RIP2 and recruitment of the linear ubiquitin chain-assembly complex (LUBAC) to Nod2 (ref. 23). However, the XIAP-mediated polyubiquitination of RIP2 is not K63 linked, a type of linkage associated with RIP2-induced activation of NF-κB. The E3 ligase Itch can also directly ubiquitinate RIP2 to negatively regulate Nod2-induced activation of NF-κB 25 . Thus, it remains unclear which E3 ubiquitin ligase directly cataly...

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“…[61][62][63][64] Several recent studies demonstrate that the E3 ligase activity of Peli proteins is also regulated by phosphorylation. [11][12][13]57 It was noted initially that IRAK1 and IRAK4 phosphorylate Peli members in transfected cells. 49,54 Using recombinant proteins and in vitro ubiquitination assays, Cohen and colleagues demonstrate that the phosphorylation of Peli proteins greatly stimulates their E3 ligase activity.…”

Section: Mechanisms Of Peli Regulationmentioning

confidence: 99%

“…9,10 Important progress has also been made to elucidate the biochemical mechanism mediating signal-induced Peli activation. [11][12][13] In this review, we discuss the recent progress on the regulation and biological functions of Peli in the context of immune receptor signaling and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

2012

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E3 ubiquitin ligases play a crucial role in regulating immune receptor signaling and modulating immune homeostasis and activation. One emerging family of such E3s is the Pelle-interacting (Peli) proteins, characterized by the presence of a cryptic forkhead-associated domain involved in substrate binding and an atypical RING domain mediating formation of both lysine (K) 63-and K48-linked polyubiquitin chains. A well-recognized function of Peli family members is participation in the signal transduction mediated by Toll-like receptors (TLRs) and IL-1 receptor. Recent gene targeting studies have provided important insights into the in vivo functions of Peli1 in the regulation of TLR signaling and inflammation. These studies have also extended the biological functions of Peli1 to the regulation of T-cell tolerance. Consistent with its immunoregulatory functions, Peli1 responds to different immune stimuli for its gene expression and catalytic activation. In this review, we discuss the recent progress, as well as the historical perspectives in the regulation and biological functions of Peli.

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The role of TBK1 and IKKϵ in the expression and activation of Pellino 1

Cited by 63 publications

References 43 publications

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

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