title: Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3.
abstract: The transcriptional regulator deformed epidermal autoregulatory factor 1 (DEAF1) has been suggested to play a role in maintaining peripheral tolerance by controlling the transcription of peripheral tissue antigen genes in lymph node stromal cells (LNSCs). Here, we demonstrate that DEAF1 also regulates the translation of genes in LNSCs by controlling the transcription of the poorly characterized eukaryotic translation initiation factor 4 gamma 3 (Eif4g3) that encodes eIF4GII. Eif4g3 gene expression was reduced in the pancreatic lymph nodes of Deaf1-KO mice, non-obese diabetic mice, and type 1 diabetes patients, where functional Deaf1 is absent or diminished. Silencing of Deaf1 reduced Eif4g3 expression, but increased the expression of Caspase 3, a serine protease that degrades eIF4GII. Polysome profiling showed that reduced Eif4g3 expression in LNSCs resulted in the diminished translation of various genes, including Anpep, the gene for aminopeptidase N, an enzyme involved in fine-tuning antigen presentation on major histocompatibility complex (MHC) class II. Together these findings suggest that reduced DEAF1 function, and subsequent loss of Eif4g3 transcription may affect peripheral tissue antigen (PTA) expression in LNSCs and contribute to the pathology of T1D.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.forename: Remi J
authors.initials: RJ
authors.lastname: Creusot
authors.forename: Cara T
authors.initials: CT
authors.lastname: Pager
authors.forename: Peter
authors.initials: P
authors.lastname: Sarnow
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D039603:Eukaryotic Initiation Factor-4G / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C548809:Deaf1 protein, mouse; C549615:Eif4g3 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; D000949:Histocompatibility Antigens Class II; D014157:Transcription Factors; C505409:Casp3 protein, mouse; D053148:Caspase 3