Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells.
Despite their low frequency, plasmacytoid dendritic cells (pDCs) produce most of the type I IFN that is detectable in the blood following viral infection. The endosomal Toll-like receptors (TLRs) TLR7 and TLR9 are required for pDCs, as well as other cell types, to sense viral nucleic acids, but the mechanism by which signaling through these shared receptors results in the prodigious production of type I IFN by pDCs is not understood. We designed a genetic screen to identify proteins required for the development and specialized function of pDCs. One phenovariant, which we named feeble, showed abrogation of both TLR-induced type I IFN and proinflammatory cytokine production by pDCs, while leaving TLR responses intact in other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine transporter 1 (PHT1) and has not previously been implicated in pDC function. The identification of the feeble mutation led to our subsequent observations that AP-3, as well as the BLOC-1 and BLOC-2 Hermansky-Pudlak syndrome proteins are essential for pDC signaling through TLR7 and TLR9. These proteins are not necessary for TLR7 or TLR9 signaling in conventional DCs and thus comprise a membrane trafficking pathway uniquely required for endosomal TLR signaling in pDCs.
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Amanda L
AL
Blasius
Carrie N
CN
Arnold
Philippe
P
Georgel
Sophie
S
Rutschmann
Yu
Y
Xia
Pei
P
Lin
Charles
C
Ross
Xiaohong
X
Li
Nora G
NG
Smart
Bruce
B
Beutler
D033963:Adaptor Protein Complex 3 / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002874:Chromosome Mapping; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005820:Genetic Testing; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*; D033921:Vesicular Transport Proteins
D033963:Adaptor Protein Complex 3; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; C554282:Hps6 protein, mouse; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C554281:Slc15a4 protein, mouse; D051193:Toll-Like Receptors; D033921:Vesicular Transport Proteins