title: Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome.
abstract: Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by dominant-negative mutations in STAT3; however, the molecular basis for mutant STAT3 allele dysfunction is unclear and treatment remains supportive. We hypothesized that AD-HIES mutations decrease STAT3 protein stability and that mutant STAT3 activity can be improved by agents that increase chaperone protein activity. We used computer modeling to characterize the effect of STAT3 mutations on protein stability. We measured STAT3 protein half-life (t1/2) and determined levels of STAT3 phosphorylated on tyrosine (Y) 705 (pY-STAT3) and mRNA levels of STAT3 gene targets in Epstein-Barr virus-transformed B (EBV) cells, human peripheral blood mononuclear cells (PBMCs), and mouse splenocytes incubated without or with chaperone protein modulators-HSF1A, a small-molecule TRiC modulator, or geranylgeranylacetone (GGA), a drug that upregulates heat shock protein (HSP) 70 and HSP90. Computer modeling predicted that 81% of AD-HIES mutations are destabilizing. STAT3 protein t1/2in EBV cells from AD-HIES patients with destabilizing STAT3 mutations was markedly reduced. Treatment of EBV cells containing destabilizing STAT3 mutations with either HSF1A or GGA normalized STAT3 t1/2, increased pY-STAT3 levels, and increased mRNA levels of STAT3 target genes up to 79% of control. In addition, treatment of human PBMCs or mouse splenocytes containing destabilizing STAT3 mutations with either HSF1A or GGA increased levels of cytokine-activated pY-STAT3 within human CD4+and CD8+T cells and numbers of IL-17-producing CD4+mouse splenocytes, respectively. Thus, most AD-HIES STAT3 mutations are destabilizing; agents that modulate chaperone protein function improve STAT3 stability and activity in T cells and may provide a specific treatment.
authors: Department of Pediatrics and.
authors: Claire E
authors: CE
authors: Bocchini
authors: Department of Pediatrics and.
authors: Karen
authors: K
authors: Nahmod
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors: Panagiotis
authors: P
authors: Katsonis
authors: Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors: Sang
authors: S
authors: Kim
authors: Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors: Moses M
authors: MM
authors: Kasembeli
authors: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors: Alexandra
authors: A
authors: Freeman
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors: Olivier
authors: O
authors: Lichtarge
authors: Department of Pediatrics and.
authors: George
authors: G
authors: Makedonas
authors: Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors: David J
authors: 0000-0001-8492-8460
authors: DJ
authors: Tweardy
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D006207:Half-Life; D000076249:Heat Shock Transcription Factors; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007589:Job Syndrome / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D004224:Diterpenes; D000076249:Heat Shock Transcription Factors; D020381:Interleukin-17; D050505:Mutant Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D019000:Phosphotyrosine; C031049:geranylgeranylacetone