The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons.
Interferon signaling pathways are critical to both innate and adaptive immunity. We have demonstrated here that the inhibition of heat shock protein 90 (Hsp90) functions by small interfering RNAs or chemical inhibitors blocking interferon-induced gene expression. Hsp90 was required for signal transducers and activators of transcription 1 phosphorylation, and in its absence, Janus kinase (JAK) 1/2 were degraded by the proteosome. JAK1 interacts with Hsp90 and the CDC37 co-chaperone, and both interactions are destabilized by Hsp90 inhibitors. The biological consequences were suggested by experiments showing that T cell activation by interferon-gamma-primed macrophages and the antiviral response of interferons required Hsp90. We conclude that JAK1/2 are client proteins of Hsp90 and that Hsp90 and CDC37 play a critical role in types I and II interferon pathways.
Shang
Limin
L
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Tomasi
Thomas B
TB
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D019013:CD40 Antigens / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000737:chemistry*; D018833:Chaperonins; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000737:chemistry* / Q000378:metabolism; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D000998:Antiviral Agents; D019013:CD40 Antigens; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007370:Interferon Type I; D016898:Interferon-alpha; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins