RT Journal Article
SR Electronic
T1 Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.22.915017
DO 10.1101/2020.01.22.915017
A1 C López-Haber
A1 R Levin-Konigsberg
A1 Y Zhu
A1 J Bi-Karchin
A1 T Balla
A1 S Grinstein
A1 MS Marks
A1 AR Mantegazza
YR 2020
UL http://biorxiv.org/content/early/2020/01/22/2020.01.22.915017.abstract
AB Toll like receptor (TLR) recruitment to phagosomes in dendritic cells (DCs) and downstream TLR signaling are essential to initiate antimicrobial immune responses. However, the mechanisms underlying TLR localization to phagosomes are poorly characterized. We show herein that phosphatidylinositol-4-kinase IIα (PI4KIIα) plays a key role in initiating phagosomal TLR4 responses in murine DCs by generating a phosphatidylinositol-4-phosphate (PtdIns4P) platform conducive to the binding of the TLR sorting adaptor TIRAP. PI4KIIα is recruited to LPS-containing phagosomes in an adaptor protein AP-3 dependent manner, and both PI4KIIα and PtdIns4P are also detected on phagosomal membrane tubules. Knockdown of PI4KIIα – but not of the related PI4KIIβ – impairs TIRAP and TLR4 localization to phagosomes, reduces proinflammatory cytokine secretion, and impairs phagosomal tubule formation and MHC-II presentation. Phagosomal TLR responses in PI4KIIα-deficient DCs are restored by re-expression of wild-type PI4KIIα, but not of variants lacking kinase activity or AP-3 binding. Our data indicate that PI4KIIα is an essential regulator of phagosomal TLR signaling in DCs by ensuring optimal TIRAP recruitment to phagosomes.