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Phosphatidylinositol 4-phosphate 5-kinase α facilitates Toll-like receptor 4-mediated microglial inflammation through regulation of the Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) location.

Authors
Nguyen, TT; Kim, YM; Kim, TD; Le, OT; Kim, JJ; Kang, HC; Hasegawa, H; Kanaho, Y; Jou, I; Lee, SY
Citation
The Journal of biological chemistry, 288(8):5645-5659, 2013
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
Abstract
Phosphatidylinositol (PI) 4,5-bisphosphate (PIP(2)), generated by PI 4-phosphate 5-kinase (PIP5K), regulates many critical cellular events. PIP(2) is also known to mediate plasma membrane localization of the Toll/IL-1 receptor domain-containing adaptor protein (TIRAP), required for the MyD88-dependent Toll-like receptor (TLR) 4 signaling pathway. Microglia are the primary immune competent cells in brain tissue, and TLR4 is important for microglial activation. However, a functional role for PIP5K and PIP(2) in TLR4-dependent microglial activation remains unclear. Here, we knocked down PIP5Kα, a PIP5K isoform, in a BV2 microglial cell line using stable expression of lentiviral shRNA constructs or siRNA transfection. PIP5Kα knockdown significantly suppressed induction of inflammatory mediators, including IL-6, IL-1β, and nitric oxide, by lipopolysaccharide. PIP5Kα knockdown also attenuated signaling events downstream of TLR4 activation, including p38 MAPK and JNK phosphorylation, NF-κB p65 nuclear translocation, and IκB-α degradation. Complementation of the PIP5Kα knockdown cells with wild type but not kinase-dead PIP5Kα effectively restored the LPS-mediated inflammatory response. We found that PIP5Kα and TIRAP colocalized at the cell surface and interacted with each other, whereas kinase-dead PIP5Kα rendered TIRAP soluble. Furthermore, in LPS-stimulated control cells, plasma membrane PIP(2) increased and subsequently declined, and TIRAP underwent bi-directional translocation between the membrane and cytosol, which temporally correlated with the changes in PIP(2). In contrast, PIP5Kα knockdown that reduced PIP(2) levels disrupted TIRAP membrane targeting by LPS. Together, our results suggest that PIP5Kα promotes TLR4-associated microglial inflammation by mediating PIP(2)-dependent recruitment of TIRAP to the plasma membrane.
MeSH terms
AnimalsCell LineCell Membrane/metabolismEnzyme-Linked Immunosorbent Assay/methodsHEK293 CellsHeLa CellsHumansInflammationInterleukin-1/metabolismMembrane Glycoproteins/metabolismMiceMicroglia/metabolismNitric Oxide/chemistryPhosphotransferases (Alcohol Group Acceptor)/*physiologyReceptors, Interleukin-1/metabolismSignal TransductionTime FactorsToll-Like Receptor 4/*metabolism
DOI
10.1074/jbc.M112.410126
PMID
23297396
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
AJOU Authors
강, 호철주, 일로이, 상윤
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