2007 Fiscal Year Final Research Report Summary
Functional Analysis of novel molecule, PRAT4 which associated with TLR4
| Project/Area Number |
18590469
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
AKASHI Sachiko The University of Tokyo, The institute of Medical Science, Assistant professor (00325599)
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| Project Period (FY) |
2006 – 2007
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| Keywords | TLR / PRAT4A / LPS |
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| Research Abstract |
Recently we have found a novel ER-resident chaperone which was discovered through co-immunoprecipitation with TLR4, PRAT4A. Although initially found as a TLR4-binding chaperone, and thusly named, PRAT4A also associates with TLR1. PRAT4A is shown to be indispensable for cell-surface expression of these TLRs. A consequence of the inability to traffic TLR4/TLR1, in the absence of PRAT4A, is that cytokine production in response to TLR4/TLR1 ligands is significantly reduced.
PRAT4A not only regulates the response of cell-surface TLR but also intracellular TLR. In the absence of PRAT4A, the response to TLR9 ligand is completely abolished. Upon CpG-B stimulation, TLR9 was reported to redistribute from the ER to CpG-B DNA-containing lysosomes. By contrast, TLR9 in PRAT4A-silenced cells have been shown to co-localize with ER marker but not with a lysosome marker or CpG-B-Rhodamine even after CpG-B stimulation. These types of experiments demonstrate a requirement for PRAT4A in ligand-induced relo
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cation/trafficking of TLR9 from the ER to lysosomal compartments.
An interesting character of PRAT4A is that PRAT4A dependency varies with each TLR. TLR7 or TLR9 mediated responses are completely dependent on PRAT4A, whereas TLR3, another nucleic acid-sensing TLR, has been shown to respond to poly (I:C) stimulation in the absence of PRAT4A. On the other hand, the responses of cell-surface TLRs seem partially dependent on PRAT4A.
Another unique character of PRAT4A is that it is indispensable for induction the endotoxin shock. Experiments have shown that PRAT4A^<-/-> BM chimeric mice are able to withstand toxic shock, in comparison to chimeric WT controls, further experiments revealed that serum cytokine levels also follow a PRAT4A-dependency. Although it remains unclear whether the lower production of cytokines is the reason for survival in PRAT4A^<-/-> BM chimeric mice or not, these results open exciting avenues of further research and the possibility that PRAT4A may become a useful target for therapeutic intervention. Less
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