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PMID:20696886

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Citation

Kim, T, Pazhoor, S, Bao, M, Zhang, Z, Hanabuchi, S, Facchinetti, V, Bover, L, Plumas, J, Chaperot, L, Qin, J and Liu, YJ (2010) Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 107:15181-6

Abstract

Toll-like receptor 9 (TLR9) senses microbial DNA and triggers type I IFN responses in plasmacytoid dendritic cells (pDCs). Previous studies suggest the presence of myeloid differentiation primary response gene 88 (MyD88)-dependent DNA sensors other than TLR9 in pDCs. Using MS, we investigated C-phosphate-G (CpG)-binding proteins from human pDCs, pDC-cell lines, and interferon regulatory factor 7 (IRF7)-expressing B-cell lines. CpG-A selectively bound the aspartate-glutamate-any amino acid-aspartate/histidine (DExD/H)-box helicase 36 (DHX36), whereas CpG-B selectively bound DExD/H-box helicase 9 (DHX9). Although the aspartate-glutamate-alanine-histidine box motif (DEAH) domain of DHX36 was essential for CpG-A binding, the domain of unknown function 1605 (DUF1605 domain) of DHX9 was required for CpG-B binding. DHX36 is associated with IFN-alpha production and IRF7 nuclear translocation in response to CpG-A, but DHX9 is important for TNF-alpha and IL-6 production and NF-kappaB activation in response to CpG-B. Knocking down DHX9 or DHX36 significantly reduced the cytokine responses of pDCs to a DNA virus but had no effect on the cytokine responses to an RNA virus. We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.

Links

PubMed PMC2930588 Online version:10.1073/pnas.1006539107

Keywords

B-Lymphocytes/immunology; B-Lymphocytes/metabolism; B-Lymphocytes/virology; Base Sequence; Binding Sites; Cell Line; CpG Islands; DEAD-box RNA Helicases/antagonists & inhibitors; DEAD-box RNA Helicases/chemistry; DEAD-box RNA Helicases/genetics; DEAD-box RNA Helicases/metabolism; DNA, Viral/metabolism; Dendritic Cells/immunology; Dendritic Cells/metabolism; Dendritic Cells/virology; Humans; Immunity, Innate; Interferon Regulatory Factor-7/metabolism; Myeloid Differentiation Factor 88/metabolism; NF-kappa B p50 Subunit/metabolism; Neoplasm Proteins/antagonists & inhibitors; Neoplasm Proteins/chemistry; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Phylogeny; Protein Structure, Tertiary; RNA, Small Interfering/genetics; Receptors, Transferrin/metabolism; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DHX9

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99836

F

Seeded From UniProt

complete

HUMAN:DHX9

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DHX9

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DHX9

involved_in

GO:0032755: positive regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MYD88

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H2U1

F

Seeded From UniProt

complete

HUMAN:MYD88

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q08211

F

Seeded From UniProt

complete

HUMAN:DHX36

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99836

F

Seeded From UniProt

complete

HUMAN:DHX36

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DHX36

involved_in

GO:0032727: positive regulation of interferon-alpha production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DHX36

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

involved_in

GO:2000778: positive regulation of interleukin-6 secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DHX9

involved_in

GO:1904469: positive regulation of tumor necrosis factor secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DHX9

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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