Protein kinase D1 is essential for MyD88-dependent TLR signaling pathway.
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-alpha 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-alpha receptor-associated factor 6; activation of TGF-beta-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.
Department of Pediatrics, Children's Foundation Research Center, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Jeoung-Eun
JE
Park
Young-In
YI
Kim
Ae-Kyung
AK
Yi
D000818:Animals; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; C089212:protein kinase D; D011493:Protein Kinase C