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TLR9 Signaling Protein Kinase D1 Protein Kinase D1: A New Component in TLR9 Signaling Jeoung-Eun Park, Young-In Kim and Ae-Kyung Yi This information is current as J Immunol 2008; 181:2044-2055; ; of September 27, 2021. doi: 10.4049/jimmunol.181.3.2044 http://www.jimmunol.org/content/181/3/2044 Downloaded from References This article cites 58 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/181/3/2044.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Protein Kinase D1: A New Component in TLR9 Signaling1 Jeoung-Eun Park,* Young-In Kim,* and Ae-Kyung Yi2*† Protein kinase D1 (PKD1) is expressed ubiquitously and regulates diverse cellular processes such as oxidative stress, gene ex- pression, cell survival, and vesicle trafficking. However, the presence and function of PKD1 in monocytic cells are currently unknown. In this study, we provide evidence that PKD1 is involved in TLR9 signaling in macrophages. Class B-type CpG DNA (CpG-B DNA) induced activation of PKD1 via a pathway that is dependent on endosomal pH, TLR9, MyD88, and IL-1R- associated kinase 1 in macrophages. Upon CpG-B DNA stimulation, PKD1 interacted with the TLR9/MyD88/IL-1R-associated kinase/TNFR-associated factor 6 complex. Knockdown of PKD1 revealed that PKD1 is required for activation of NF-␬B and MAPKs, and subsequent expression of cytokines in response to CpG-B DNA. Our findings identify PKD1 as a key signaling modulator in TLR9-mediated macrophage activation. The Journal of Immunology, 2008, 181: 2044–2055. he success of host defense against microbial infection de- with and activating Tank-binding kinase 1 and IFN regulatory fac- Downloaded from pends on the capacity of innate immune cells to detect tor (IRF) 3 (6, 8, 9). In contrast, TLR9 recognizes both single- and T invading pathogens. Innate immune cells express groups dsDNA with synthetic phosphorothioate backbones as well as na- of structurally related proteins called pattern recognition receptors tive phosphodiester backbones via an endosomal pH-sensitive and (PRR)3 such as TLR-family proteins, NACHT-leucine-rich repeat- DNA sequence-specific (unmethylated CpG motif) manner in en- family proteins, and helicase domain-containing antiviral proteins dosomal compartments, and its signal transduction requires an (1–4). Recognition of the evolutionally conserved structures in adaptor molecule, MyD88 (10). Most, if not all, known biologic http://www.jimmunol.org/ microorganisms (pathogen-associated molecular patterns), includ- effects of the unmethylated CpG motifs containing bacterial DNA ing LPS and microbial nucleic acids, by PRRs in innate immune or synthetic DNA are mediated through a TLR9/MyD88-signaling cells initiates the complex signaling cascades leading to secretion pathway. Ligand (CpG motif containing DNA)-bound TLR9 re- of proinflammatory cytokines and mediators that control growth cruits MyD88 and initiates a signaling pathway that sequentially and dissemination of invading pathogens. involves IL-1R-associated kinase (IRAK) 4, IRAK1, TNF-␣ re- DNA released by bacterial and viral pathogens is recognized by ceptor-associated factor (TRAF) 6, and TRAF3 (2, 11). Activation host cells through at least two different mechanisms: the TLR9 of TRAF6 and TRAF3 initiates signaling cascades that lead to pathway and the cytosolic DNA pathway (5–7). In the cytosolic activation of NF-␬B, MAPKs, and IRFs, and subsequent expres- DNA pathway, the yet to be discovered cytosolic DNA receptor sion of various proinflammatory cytokines, chemokines, and on- by guest on September 27, 2021 recognizes dsDNA with a native phosphodiester backbone in a cogenes. In addition to this well-defined TLR9/MyD88-signaling DNA sequence-independent manner in cytoplasm. It induces pro- pathway, CpG motif-containing DNA has also been shown to in- duction of type I IFN and other immune responses by interacting duce generation of reactive oxygen species (ROS) and activation of Ras and Vav1 (12–15). The mechanisms by which the CpG motif containing DNA activate these additional signaling modu- *Children’s Foundation Research Center at Le Bonheur Children’s Medical Center lators are yet to be revealed. and Department of Pediatrics, University of Tennessee Health Science Center, Mem- phis, TN 38103; and †Department of Molecular Sciences, University of Tennessee The protein kinase D (PKD) family is a group of three struc- Health Science Center, Memphis, TN 38163 turally related serine/threonine kinases: PKD1/protein kinase C␮ Received for publication February 6, 2008. Accepted for publication May 18, 2008. (PKC␮), PKD2, and PKD3/PKC␯ (16). PKDs are expressed ubiq- The costs of publication of this article were defrayed in part by the payment of page uitously, including in B and T lymphocytes (17, 18). PKDs can be charges. This article must therefore be hereby marked advertisement in accordance activated by upstream signaling modulators such as PI3K, phos- with 18 U.S.C. Section 1734 solely to indicate this fact. pholipase C␥ (PLC␥), diacylglycerol, and classical/novel PKCs 1 A.-K.Y. was supported by the Children’s Foundation Research Center at Le Bon- that are activated through signals transduced by G-protein cou- heur Children’s Medical Center, and grants from the National Institutes of Health (AI053137, AR47757) and the Children’s Foundation of Memphis. J.-E.P. was sup- pled-receptor agonists, ROS, epidermal growth factor receptor, ported by a grant from Le Bonheur Children’s Medical Center. Y.-I.K. was supported Fc␥RII, BCR, and TCR (18–24). Depending on the cell context by a Postdoctoral Fellowship from the Korea Research Foundation (KRF-2005-214- and the stimulation conditions, PKDs display dynamic changes in E00045) and a grant from Le Bonheur Children’s Medical Center. Animal experi- ments were supported in part by a Transgenic Mice Program grant from the Chil- intracellular locations. They can be located in cytosol, the plasma dren’s Foundation of Memphis. membrane, the mitochondria, the Golgi apparatus, or the nucleus 2 Address correspondence and reprint requests to Dr. Ae-Kyung Yi, Department of (20, 25–30). Cellular location of PKDs has been shown to dictate Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap Street, Room 315, Memphis, TN 38103. E-mail address: [email protected] the biological role of the protein. PKDs have been demonstrated to be implicated in the regulation of a variety of cellular and subcel- 3 Abbreviations used in this paper: PRR, pattern recognition receptor; IRF, IFN reg- ulatory factor; IRAK, IL-1R-associated kinase; TRAF, TNFR-associated factor; ROS, lular processes such as vesicle transportation, ROS generation, ac- reactive oxygen species; PKD, protein kinase D; PLC, phospholipase C; PKC, protein tivation of MAPKs and NF-␬B, and regulation of cell shape, mo- kinase C; DC, dendritic cell; KC, Kupffer cell; cDC, conventional DC; pDC, plas- macytoid DC; ODN, oligodeoxynucleotide; S-ODN, nuclease-resistant phosphoro- tility, adhesion, and gene expression (18, 20, 29–33). There have thioate ODN; EC, E. coli; CT, calf thymus; PTK, protein tyrosine kinase; mCsk, been a couple of studies that indicate a possibility that PKD family membrane-targeted form of C-terminal Src kinase; TIR, Toll/IL-1R; shRNA, small members may be involved in TLR signaling in nonimmune cells. hairpin interfering RNA. LPS-mediated p38 activation and TNF-␣ secretion in microglial Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 cells is suppressed by a PKC/PKD inhibitor, Go¨6976 (34). PKD1 www.jimmunol.org The Journal of Immunology 2045 has been shown to bind and phosphorylate TLR5, and Go¨6976 detectable endotoxins by Limulus assay. Sequences of S-ODN were pre- suppresses flagellin-mediated p38 activation and IL-8 production viously reported (37–40). Escherichia coli (EC) DNA, calf thymus (CT) in epithelial cells (35). However, to date, there is no evidence that DNA, and EGTA were purchased from Sigma-Aldrich. PP1 was purchased from Invitrogen. SU6656, LY294002, U73122, Go¨6976, Go¨6983, and pathogenic DNA induces activation of PKD family members, and Go¨6850 were purchased from Calbiochem. it is not known whether innate immune cells like macrophages express PKD family proteins and whether PKD family members play an active role in macrophage activation induced by patho- Plasmids, generation of FLAG-tagged PKD-expressing genic DNA. In this study, we demonstrate that macrophages ex- macrophages and gene-specific knockdown macrophages, press all three PKD family members and that bacterial DNA and transient transfection, reporter gene assay, and RT-PCR class B type CpG DNA (CpG-B DNA) induce activation of PKD1. To make the FLAG-tagged PKD1, PKD2, and PKD3 constructs, the In addition, we have identified a part of the biochemical mecha- coding regions of PKD1, PKD2, and PKD3 were amplified by PCR and nisms by which CpG-B DNA activates PKD1 and the biologic then subcloned into pIRES-hrGFPII vector (Stratagene). DNA se- quences of all cloned genes were confirmed by DNA-sequencing anal- functions of PKD1 in macrophages. ysis and were identical with the previously reported sequences.
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