A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A-/- mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A-/- bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.
Takahashi
Koichiro
K
Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Shibata
Takuma
T
Akashi-Takamura
Sachiko
S
Kiyokawa
Takashi
T
Wakabayashi
Yasutaka
Y
Tanimura
Natsuko
N
Kobayashi
Toshihiko
T
Matsumoto
Fumi
F
Fukui
Ryutaro
R
Kouro
Taku
T
Nagai
Yoshinori
Y
Takatsu
Kiyoshi
K
Saitoh
Shin-ichiroh
S
Miyake
Kensuke
K
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D020868:Gene Silencing; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D002352:Carrier Proteins; C508076:TLR4-associated protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4