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Transduction TLR4- Versus TLR2-Mediated Signal Domain Differential Involvement of BB Loops of Toll-IL-1 Resistance (TIR) Domain-Containing Adapter Proteins in TLR4- versus TLR2-Mediated Signal This information is current as Transduction of September 28, 2021. Vladimir U. Toshchakov, Subhendu Basu, Matthew J. Fenton and Stefanie N. Vogel J Immunol 2005; 175:494-500; ; doi: 10.4049/jimmunol.175.1.494 Downloaded from http://www.jimmunol.org/content/175/1/494 References This article cites 44 articles, 17 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/175/1/494.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Involvement of BB Loops of Toll-IL-1 Resistance (TIR) Domain-Containing Adapter Proteins in TLR4- versus TLR2-Mediated Signal Transduction1 Vladimir U. Toshchakov,* Subhendu Basu,† Matthew J. Fenton,2*† and Stefanie N. Vogel2,3*† TLRs sense pathogens and transmit intracellular signals via the use of specific adapter proteins. We designed a set of “blocking peptides” (BPs) comprised of the 14 aa that correspond to the sequences of the BB loops of the four known Toll-IL-1 resistance (TIR) domain-containing adapter proteins (i.e., MyD88, TIR domain-containing adapter inducing IFN-␤ (TRIF), TRIF-related adapter molecule (TRAM), and TIR-domain containing adapter protein (TIRAP)) linked to the cell-penetrating segment of the antennapedia homeodomain. LPS (TLR4)-mediated gene expression, as well as MAPK and transcription factor activation asso- ciated with both MyD88-dependent and -independent signaling pathways, were disrupted by all four BPs (TRAM Ϸ MyD88 > Downloaded from TRIF > TIRAP), but not by a control peptide. In contrast, none of the BPs inhibited TLR2-mediated activation of MAPKs. Only the MyD88 BP significantly blocked Pam3Cys-induced IL-1␤ mRNA; however, the inhibitory effect was much less than observed for LPS. Our data suggest that the interactions required for a fully functional TLR4 signaling “platform” are disrupted by these BPs, and that the adapter BB loops may serve distinct roles in TLR4 and TLR2 signalosome assembly. The Journal of Immu- nology, 2005, 175: 494–500. http://www.jimmunol.org/ oll-like receptors are a family of signaling molecules that domain-containing adapter molecule-1 (7); and TRIF-related act as sensors for recognition of diverse pathogen-asso- adapter molecule (TRAM) (8), also named as TIR-containing pro- T ciated molecular patterns. All TLRs share a similar do- tein (9) or TIR domain-containing adapter molecule-2 (10). main architecture: an extracellular region that contains multiple MyD88 and TRIF have a more complex domain architecture leucine-rich repeat regions (1) that function in recognition of than TIRAP and TRAM. In addition to the TIR domain, MyD88 pathogen-associated molecular patterns and coreceptors (2); a has a mid-region and an N-terminal death domain that enable in- transmembrane domain comprised of one membrane-spanning teraction with IL-1R-associated kinase 4 (IRAK-4) and IRAK-1, ␣-helix; and an intracellular “Toll-IL-1 resistance” (TIR)4 domain respectively, serine/threonine kinases that signal downstream of located within the C terminus (1). IL-1R (11) and TLRs (3), leading to NF-␬B activation (reviewed by guest on September 28, 2021 In addition to TLRs, a group of TIR domain-containing proteins in Ref. 12). TRIF is the largest member of adapter family, with the that lack a transmembrane domain has been identified. MyD88 was TIR domain located in the middle of its sequence. The N terminus the first TIR domain-containing protein that was shown to serve as of TRIF is necessary for activation of NF-␬B and IFN regulatory an adapter for IL-1R, and later, for TLR signaling (3). With rapid factor (IRF)-3 (6), a transcription factor responsible for induction progress in sequencing and gene annotation, this family grew of IFN-␤ and other genes. I␬B kinase (IKK)-⑀ and TRAF family quickly and now includes five members, four of which are in- member-associated NF-␬B binding kinase (TANK)-binding ki- volved in TLR4 signaling: MyD88; TIR-domain containing nase-1 (TBK-1), act downstream of TRIF to phosphorylate IRF-3 adapter protein (TIRAP) (4), also known as Mal (5); TIR domain- (13). Recruitment of IKK-⑀ and TBK-1 to TRIF does not require containing adapter inducing IFN-␤ (TRIF) (6), also referred as TIR TIR domain of the protein (8), and overexpression of a TRIF mu- tant that lacks the C terminus still activates NF-␬B and IFN-␤ reporter constructs (6, 7). *Department of Microbiology and Immunology and †Department of Medicine, Uni- versity of Maryland, Baltimore, MD 21201 TIRAP and TRAM are the smallest adapters involved in TLR Received for publication January 10, 2005. Accepted for publication April 16, 2005. signaling. The N terminus of TRAM has a myristoylation site, the The costs of publication of this article were defrayed in part by the payment of page mutation of which alters its normal membrane localization (14). charges. This article must therefore be hereby marked advertisement in accordance Both TIRAP and TRAM have been found to associate constitu- with 18 U.S.C. Section 1734 solely to indicate this fact. tively with TLR4 (5, 8). Current models of TLR signaling ascribe 1 This work was supported by National Institutes of Health Grants AI-18797 and different roles to the adapters (10, 14). TIRAP and TRAM have AI-44936 (to S.N.V.) and AI-57490 (to M.J.F.). been suggested to serve as “platform-forming” components re- 2 M.J.F. and S.N.V. contributed equally to this work. sponsible for recruitment of the larger adapters, MyD88 and TRIF, 3 Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Depart- respectively, that in turn, recruit downstream effector molecules ment of Microbiology and Immunology, University of Maryland, Baltimore, 655 West Baltimore Street, 13-009, Baltimore, MD 21201. E-mail address: (e.g., IRAK-1 and IRAK-4 to MyD88 and TBK-1, TRAF6, and [email protected] IKK-⑀ to TRIF via non-TIR domains). Distinct combinations of 4 Abbreviations used in this paper: TIR, Toll-IL-1 resistance; BP, blocking peptide; adapters involved in a signaling platform differ among TLRs and CP, control peptide; TIRAP, TIR-domain containing adapter protein; TRIF, TIR do- have been postulated as the basis for the observed specificity of main-containing adapter inducing IFN-␤; TRAM, TRIF-related adapter molecule; TBK-1, TRAF family member-associated NF-␬B binding kinase (TANK)-binding gene subsets induced by different TLR agonists (see Refs. 14 and ⑀ ␬ ⑀ kinase-1; IKK- ,I B kinase ; IRAK-1/4, IL-1R-associated kinase 1/4; Pam3Cys, 15 for review). (S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-Ser-Lys4-OH); HPRT, hy- poxanthine phosphoribosyltransferase; IRF, IFN regulatory facto; GI, GenBank ID The structure of TLR TIR domains was first predicted by Rock number. et al. (1). Analysis of sequences of five human TLRs and their Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 495 diverse homologues led the authors to conclude that TIR domains ited TLR2-mediated induction of IL-1␤ mRNA; however, its in- are composed of five ␤-strands alternating with five ␣-helices. hibitory effect was considerably weaker than its effect on TLR4- Resolution of crystal structures of human TLR1 and TLR2 con- mediated IL-1␤ gene expression. Collectively, our findings firmed these theoretical findings and suggested that a functionally suggest that these BPs interfere with protein-protein interactions important proline-glycine combination that is highly conserved involved in the assembly and/or stabilization of the TLR4 “plat- among TIR domains is located in the loop connecting the second form” and support the hypothesis that surfaces on MyD88 and ␤-strand with the second helix, the “BB loop,” using the termi- TIRAP apart from the BB loop enable their interaction with TLR2. nology proposed by Xu et al. (16). The importance of BB loops in TLR signaling derives from Materials and Methods observations that the function of TIR domain-containing proteins Animals is highly susceptible to mutations in this region. A naturally oc- curring point mutation (P712H) in murine TLR4, which leads to C3H/OuJ mice were purchased from The Jackson Laboratory. Thioglyco- late-elicited peritoneal macrophages were harvested and cultured in the complete unresponsiveness of the C3H/HeJ mouse to LPS (17, presence of Escherichia coli K235 LPS or (S-[2,3-bis(palmitoyloxy)-(2- 681 18), lies in this region. Similarly, replacement of Pro with His RS)-propyl]-N-palmitoyl-(R)-Cys-Ser-Lys4-OH) (Pam3Cys) as described in human TLR2 was reported to disrupt signal transduction in- previously (29). duced by Gram-positive bacteria and essentially abolishes MyD88 Design of peptides recruitment (16); however, this finding was not confirmed by Dunne et al. (19). Mutations of residues in the vicinity of the The peptides were composed of 16-aa carrier sequence from Drosophila conserved BB loop proline also led to the decreased activity of homeodomain protein (aa 366–381, GenBank ID number (GI): 4389425), Downloaded from the C terminus of which was synthesized in tandem with the N terminus of TLR2 (16) and TLR4 (20).
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