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Protein Kinase D1 Is Essential for MyD88-Dependent TLR Signaling Pathway¹

Jeoung-Eun Park^*, Young-In Kim^* and Ae-Kyung Yi^2,*,

^* Children’s Foundation Research Center, Le Bonheur Children’s Medical Center and Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103; and Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163

Protein kinase D1 (PKD1) has been shown to be involved in certain MAPK activation and cytokine expression by several TLR ligands. However, the precise physiological role of PKD1 in individual signaling from TLRs has not been fully addressed. In this study, we provide evidence that PKD1 is being activated by TLR ligands, except the TLR3 ligand. PKD1 activation by TLR ligands is dependent on MyD88, IL-1R-associated kinase 4 and 1, but independent of TNF- receptor-associated factor 6. PKD1-knockdown macrophages and bone marrow-derived dendritic cells revealed that PKD1 is indispensable for the MyD88-dependent ubiquitination of TNF- receptor-associated factor 6; activation of TGF-β-activated kinase 1, MAPKs, and transcription factors; and expression of proinflammatory genes induced by TLR ligands, but is not involved in expression of type I IFNs induced by TLR ligands and TRIF-dependent genes induced by TLR3 and TLR4 ligands. These results demonstrate that PKD1 is essential for MyD88-dependent proinflammatory immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A.-K.Y. was supported by the Children’s Foundation Research Center at Le Bonheur Children’s Medical Center, and grants from National Institutes of Health (AI053137) and the Children’s Foundation of Memphis. Y.-I.K. and J.-E.P. were supported by grants from Le Bonheur Children’s Medical Center. Animal experiments were supported in part by transgenic mice program grant from the Children’s Foundation of Memphis.

² Address correspondence and reprint requests to Dr. Ae-Kyung Yi, Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap Street, LBCMC Room 315, Memphis, TN 38103. E-mail address: ayi{at}utmem.edu

³ Abbreviations used in this paper: TIR, Toll/IL-1R; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; FSL-1, diacylated synthetic lipopeptide; IP-10, IFN--inducible protein 10; IRAK, IL-1R-associated kinase; IRF, IFN regulatory factor; ISRE, IFN-stimulated responsive element; MAL, MyD88 adaptor-like; MDP, muramyl dipeptide; Pam₃CSK₄, palmitoyl-3-cysteine-serine-lysine-4; PGN, peptidoglycan; PKC, protein kinase C; PKD, protein kinase D; shRNA, small hairpin interfering RNA; siRNA, small interfering RNA; TAK1, TGF-β-activated kinase 1; TIRAP, TIR domain-containing adaptor protein; TRAF, TNF- receptor-associated factor; TRIF, TIR domain-containing adaptor-inducing IFN-β.