Hsp90 binds CpG oligonucleotides directly: implications for Hsp90 as a missing link in CpG signaling and recognition

Bandholtz, Lisa; Guo, Yaxin; Palmberg, Carina; Mattsson, Kristin; Ohlsson, Björn; High, Anthony A.; Shabanowitz, Jeffrey; Hunt, Donald F.; Jörnvall, Hans; Wigzell, Hans; Agerberth, Birgitta; Guðmundsson, Guðmundur H.

doi:10.1007/s000180300035

Cited by 40 publications

(20 citation statements)

References 27 publications

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“…Recently, Hsp90 has been implicated in facilitating this recognition (38). Therefore, Hsp90 probably acts as a ligand transfer molecule bridging the receptor-ligand gap in this system (38). We envisage a similar role for Hsp90 in N-mediated resistance to TMV and in broader R protein signaling.…”

Section: Discussionmentioning

confidence: 78%

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Molecular Chaperone Hsp90 Associates with Resistance Protein N and Its Signaling Proteins SGT1 and Rar1 to Modulate an Innate Immune Response in Plants

Liu¹,

Burch‐Smith²,

Schiff

et al. 2004

Journal of Biological Chemistry

314

268

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SGT1 and Rar1 are important signaling components of resistance (R) gene-mediated plant innate immune responses. Here we report that SGT1 and Rar1 associate with the molecular chaperone Hsp90. In addition, we show that Hsp90 associates with the resistance protein N that confers resistance to tobacco mosaic virus. This suggests that Hsp90-SGT1-Rar1 and R proteins might exist in one complex. Suppression of Hsp90 in Nicotiana benthamiana plants shows that it plays an important role in plant growth and development. In addition, Hsp90 suppression in NN plants compromises N-mediated resistance to tobacco mosaic virus. Our results reveal a new role for SGT1-and Rar1-associated chaperone machinery in R gene-mediated defense signaling.

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Section: Discussionmentioning

confidence: 78%

“…TLR9 is known to recognize unmethylated bacterial CpG DNA to initiate defense (37). Recently, Hsp90 has been implicated in facilitating this recognition (38). Therefore, Hsp90 probably acts as a ligand transfer molecule bridging the receptor-ligand gap in this system (38).…”

Section: Discussionmentioning

confidence: 99%

Molecular Chaperone Hsp90 Associates with Resistance Protein N and Its Signaling Proteins SGT1 and Rar1 to Modulate an Innate Immune Response in Plants

Liu¹,

Burch‐Smith²,

Schiff

et al. 2004

Journal of Biological Chemistry

314

268

View full text Add to dashboard Cite

show abstract

“…High affinity and specific binding of LPS to gp96 has been shown in a recent study (46). Furthermore, HSP90 has been suggested to act as a primary receptor for immunostimulatory bacterial CpG DNA and to deliver these ligands to the TLR9 complex (47). An important biological function of mammalian chaperones seems possible, i.e., improvement of recognition of microbial structures by innate immune cells.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 60: Specific Binding of Lipopolysaccharide

Habich

Kempe

Zee

et al. 2005

The Journal of Immunology

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Human heat shock protein 60 (HSP60) has been shown to bind to the surface of innate immune cells and to elicit a proinflammatory response. In this study we demonstrate that the macrophage stimulatory property of recombinant human HSP60 is tightly linked to the HSP60 molecule and is lost after protease treatment. However, inhibition of macrophage stimulation was reached by the LPS-binding peptide magainin II amide. Indeed, HSP60 specifically bound [3H]LPS. [3H]LPS binding to HSP60 was saturable and competable by the unlabeled ligand. To identify the epitope region of the HSP60 molecule responsible for specific LPS binding, we analyzed the effect of several anti-HSP60 mAbs on HSP60-induced production of inflammatory mediators from macrophages. We identified only one mAb, clone 4B9/89, which blocked the macrophage stimulatory activity of the chaperone. The epitope specificity of this mAb points to the region aa 335–366 of HSP60. Clone 4B9/89 also strongly inhibited [3H]LPS binding to HSP60. A more detailed analysis was performed by screening with selected overlapping 20-mer peptides of the HSP60 sequence, covering the region aa 331–380. Only one peptide blocked LPS binding to HSP60, thereby restricting the potential LPS-binding region to aa 351–370 of HSP60. Finally, analysis of selected 15-mer peptides and a 13-mer peptide of the HSP60 sequence revealed that most of the LPS-binding region was accounted for by aa 354–365 of HSP60, with the motif LKGK being critical for binding. Our studies identified a defined region of HSP60 involved in LPS binding, thereby implicating a physiological role of human HSP60 as LPS-binding protein.

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“…The mechanism by which a methylated plasmid is detected by immune cells still remains unknown. Recent studies have described that HSP90 and lactoferrin interact as well as with unmethylated and methylated DNA [46,47]. In addition, type A Scavenger receptor binds polyanionic compounds such DNA [48].…”

Section: Discussionmentioning

confidence: 99%

Methylated CpG‐Containing Plasmid Activates the Immune System

et al. 2004

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Bacterial DNA differs from mammalian DNA by the presence of unmethylated cytosine-phosphate-guanosine (CpG) motifs. The immunostimulatory properties of a DNA vaccine have been suspected to be associated with these motifs. The aim of this study was to assess the inactivation of the immunostimulatory potential of a plasmid after methylation of its CpG motifs. We constructed two identical non-coding plasmids, and one of these was de novo methylated on its CG sequences. A single administration of recombinant antigen with methylated or unmethylated CpG-containing plasmid was performed in mice. As expected, only unmethylated CpG-containing plasmid enhanced the specific immune response. However, a study of in vivo activation of Langerhans' cells and analysis of mRNA synthesis indicated that both the plasmids promoted cell emigration and cytokine induction. These data highlight that a methylated CpG-containing plasmid is not inert and carries immunomodulatory properties. The results further emphasize the necessity to definitively identify the mode of action of plasmids used for DNA vaccination.

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Hsp90 binds CpG oligonucleotides directly: implications for Hsp90 as a missing link in CpG signaling and recognition

Cited by 40 publications

References 27 publications

Molecular Chaperone Hsp90 Associates with Resistance Protein N and Its Signaling Proteins SGT1 and Rar1 to Modulate an Innate Immune Response in Plants

Molecular Chaperone Hsp90 Associates with Resistance Protein N and Its Signaling Proteins SGT1 and Rar1 to Modulate an Innate Immune Response in Plants

Heat Shock Protein 60: Specific Binding of Lipopolysaccharide

Methylated CpG‐Containing Plasmid Activates the Immune System

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