title: Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.
abstract: Peripheral tolerance is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs). We previously identified a transcriptional regulator, deformed epidermal autoregulatory factor 1 (Deaf1), that can regulate PTA expression in LNSCs of the pancreatic lymph nodes (PLNs). During the pathogenesis of type 1 diabetes (T1D), Deaf1 is spliced to form the dominant-negative isoform Deaf1-Var1. Here we show that Deaf1-Var1 expression correlates with the severity of disease in NOD mice and is reduced in the PLNs of mice that do not develop hyperglycemia. Inflammation and hyperglycemia independently drive Deaf1 splicing through activation of the splicing factors Srsf10 and Ptbp2, respectively. Inflammation induced by injection of activated splenocytes increased Deaf1-Var1 and Srsf10, but not Ptbp2, in the PLNs of NOD.SCID mice. Hyperglycemia induced by treatment with the insulin receptor agonist S961 increased Deaf1-Var1 and Ptbp2, but not Srsf10, in the PLNs of NOD.B10 and NOD mice. Overexpression of PTBP2 and/or SRSF10 also increased human DEAF1-VAR1 and reduced PTA expression in HEK293T cells. These data suggest that during the progression of T1D, inflammation and hyperglycemia mediate the splicing of DEAF1 and loss of PTA expression in LNSCs by regulating the expression of SRSF10 and PTBP2.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA lindayip@stanford.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fuhlbrigge
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Cariel
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Department of Medicine, Columbia Center for Translational Immunology and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY.
authors.forename: Remi J
authors.initials: RJ
authors.lastname: Creusot
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Nishikawa-Matsumura
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Chan C
authors.initials: CC
authors.lastname: Whiting
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Schartner
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: Rahima
authors.initials: R
authors.lastname: Akter
authors.affiliation: Type 1 Diabetes Center, The La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000375:Aging; D017398:Alternative Splicing; D000818:Animals; D001786:Blood Glucose; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008198:Lymph Nodes / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000502:physiology; D010196:Pancreatic Elastase / Q000235:genetics / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D018797:Cell Cycle Proteins; C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; C548809:Deaf1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C504334:PTBP2 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C115188:SRSF10 protein, human; D014157:Transcription Factors; D038941:Polypyrimidine Tract-Binding Protein; D000068103:Serine-Arginine Splicing Factors; C000595173:CELA1 protein, human; D010196:Pancreatic Elastase