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      Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production

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      , ,
      Nature immunology

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          Abstract

          Toll-like receptors (TLRs) play a pivotal role in innate immunity and inflammation. Here we showed that genetic deficiency of Peli1, an E3 ubiquitin ligase, attenuates induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and renders mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IκB kinase (IKK) and its downstream target transcription factor NF-κB, but was dispensable for IKK–NF-κB activation induced by several other TLRs and the interleukin-1 receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. These findings suggest that Peli1 is a ubiquitin ligase needed for transmission of TRIF-dependent TLR signals.

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          Most cited references34

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          Triggering the interferon antiviral response through an IKK-related pathway.

          Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.
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            TLR signaling.

            The TLR family senses the molecular signatures of microbial pathogens, and plays a fundamental role in innate immune responses. TLRs signal via a common pathway that leads to the expression of diverse inflammatory genes. In addition, each TLR elicits specific cellular responses to pathogens owing to differential usage of intracellular adapter proteins. Recent studies have revealed the importance of the subcellular localization of TLRs in pathogen recognition and signaling. TLR signaling pathways is negatively regulated by a number of cellular proteins to attenuate inflammation. Here, we describe recent advances in our understanding of the regulation of TLR-mediated signaling.
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              Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.

              MyD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MyD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MyD88 adapter-like, a second adapter harboring the TIR domain, is essential for MyD88-dependent TLR2 and TLR4 signaling pathways, but not for MyD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-beta (TRIF). As is the case in MyD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MyD88-independent pathway.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature immunology
                1529-2908
                1529-2916
                21 August 2009
                6 September 2009
                October 2009
                1 April 2010
                : 10
                : 10
                : 1089-1095
                Affiliations
                Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston TX 77030
                Author notes
                [1]

                these authors contributed equally to this work

                Correspondence should be addressed to S.-C.S. ( ssun@ 123456mdanderson.org )
                Article
                nihpa137914
                10.1038/ni.1777
                2748822
                19734906
                432c1413-bd0f-4f8d-880d-fd80f6b8c2c4

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 GM084459-08 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI064639-04 ||AI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057555-06 ||AI
                Categories
                Article

                Immunology
                Immunology

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