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

Takahashi, Koichiro; Shibata, Takuma; Akashi-Takamura, Sachiko; Kiyokawa, Takashi; Wakabayashi, Yasutaka; Tanimura, Natsuko; Kobayashi, Toshihiko; Matsumoto, Fumi; Fukui, Ryutaro; Kouro, Taku; Nagai, Yoshinori; Takatsu, Kiyoshi; Saitoh, Shin-Ichiroh; Miyake, Kensuke

doi:10.1084/jem.20071132

Cited by 166 publications

(171 citation statements)

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“…TLR9-GFP expressed in M12 B cell lymphoma was compared with that in PRAT4A-silenced M12 cells. PRAT4A is a TLR-specific chaperone 18 , and TLR9 fails to exit the ER and therefore remains unprocessed in the absence of PRAT4A. The fragment missing in PRAT4A-silenced M12 cells is therefore likely to be TLR9C (Fig.…”

Section: Resultsmentioning

confidence: 99%

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

et al. 2013

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Toll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N þ C. The TLR9-dependent cytokine production by Tlr9 À / À dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N þ C complex is a bona fide DNA sensor.

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Section: Resultsmentioning

confidence: 99%

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

et al. 2013

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“…A protein associated with TLR4 (PRAT4A) was also reported to play a role in the process of TLR4 maturation/glycosylation in bone marrow-derived macrophages (20,21). PRAT4A likely a component of the machinery facilitating TLR4/MD-2 trafficking to the cell surface (19,22). Trafficking of TLR4 to the membrane of macrophages in response to LPS is also shown to be reactive oxygen species-dependent (23), and heme oxygenase-1/CO suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1 (24).…”

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Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Rocuts

Zhang

et al. 2010

The Journal of Immunology

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Islet allografts from donor mice exposed to CO are protected from immune rejection after transplantation via the suppression of membrane trafficking/activation of TLR4 in islets/β cells. The molecular mechanisms of how CO suppresses TLR4 activation in β cells remain unclear and are the focus of this study. Cells of the insulinoma cell line, βTC3, were stably transfected with pcDNA3-TLR4-YFP and pDsRed-Monomer-Golgi plasmids and used to identify the subcellular distribution of TLR4 before and after LPS stimulation by confocal microscopy. Immunofluorescence analysis revealed that TLR4 mainly resides in the Golgi apparatus in βTC3 cells when in a quiescent state. LPS stimulation led to a rapid trafficking of TLR4 from the Golgi to the cell membrane. Physical interaction between TLR4 and myeloid differentiation factor-2 (MD-2) was confirmed by immunoprecipitation. Depleting MD-2 using small interfering RNA or blocking the N-glycosylation of cells using tunicamycin blocked membrane trafficking of TLR4. Pre-exposing cells to CO at a concentration of 250 parts per million suppressed membrane trafficking of TLR4 via inhibiting its glycosylation and the interaction between TLR4 and MD-2. In conclusion, MD-2 is required for the glycosylation of TLR4 and its consequent membrane trafficking in βTC3 cells. CO suppresses membrane activation of TLR4 via blocking its glycosylation and the physical interaction between TLR4 and MD-2.

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“…Also known as PRAT4A (protein associated with TLR4 A), CNPY3 can regulate TLR4 signaling and cell surface expression (3). Its role in regulating TLR1, TLR2, TLR5, TLR7, and TLR9 was also later uncovered (4,5). Curiously, similar to gp96, CNPY3 does not appear to play a role in TLR3 regulation (4).…”

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“…Its role in regulating TLR1, TLR2, TLR5, TLR7, and TLR9 was also later uncovered (4,5). Curiously, similar to gp96, CNPY3 does not appear to play a role in TLR3 regulation (4). The characterization of three single-nucleotide polymorphisms (R95L, S231I, and M145K) in CNPY3 led to the discovery that M145K could alter function (6).…”

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confidence: 99%

Drosophila canopy b is a cochaperone of glycoprotein 93

Morales

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillDrosophila gp93 was identified as the ortholog of the mammalian endoplasmic reticulum-resident chaperone gp96. gp93 was found capable of rescuing gp96 client proteins, such as Tolllike receptors (TLRs) and integrins, in a gp96-deficient murine cell line. Mammalian gp96 was further found to require the cochaperone canopy 3 (CNPY3) for proper folding and expression of TLRs, but not integrins. In Drosophila, two possible CNPY family members have been identified but have not yet been characterized. Therefore, we sought to determine the role of Drosophila CNPYa and CNPYb in gp93 biology. Because of higher similarities between CNPY3 and CNPYb, we postulated that CNPYb would be a TLR-specific cochaperone of gp93. Indeed, CNPYb addition in gp93-expressing cells improved TLR expression. CNPYb and gp93 were further found to physically interact. Mutational analysis of cysteine residues in CNPYb identified differential dependence of these cysteines in chaperone function. Our study is the first to characterize Drosophila CNPY molecules. We further uncover more gp93 biology by identifying CNPYb as a cochaperone. A better understanding of this simpler Drosophila system will enable application to the mammalian system, such as has been done with Escherichia coli, yeast, and mammalian HSP90.

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

Cited by 166 publications

References 31 publications

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Drosophila canopy b is a cochaperone of glycoprotein 93

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