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A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.

J.Exp.Med. 204: 2963-2976, 2007
Koichiro Takahashi,1,3 Takuma Shibata,1,3 Sachiko Akashi-Takamura,1,3 Takashi Kiyokawa,1 Yasutaka Wakabayashi,1 Natsuko Tanimura,1 Toshihiko Kobayashi,1 Fumi Matsumoto,1 Ryutaro Fukui,1 Taku Kouro,2,4 Yoshinori Nagai,2,4 Kiyoshi Takatsu,2,4 Shin-ichiroh Saitoh,1 and Kensuke Miyake1
1: Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo
2: Division of Immunology, The Institute of Medical Science, The University of Tokyo
4: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
3: These authors contributed equally to this study.

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.