Reinaldo S Dos Santos1,2,3, Laura Marroqui1,2,3, Teresa Velayos3,4,5, Ane Olazagoitia-Garmendia4,6, Amaia Jauregi-Miguel4,6, Ainara Castellanos-Rubio3,4,6, Decio L Eizirik1, Luis Castaño3,4,5,7, Izortze Santin8,9,10,11. 1. ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium. 2. Instituto de Biología Molecular y Celular (IBMC), and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain. 3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. 4. Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. 5. Department of Pediatrics, University of the Basque Country, Leioa, Spain. 6. Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, Leioa, Spain. 7. CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 8. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. izortze.santin@ehu.eus. 9. Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. izortze.santin@ehu.eus. 10. CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. izortze.santin@ehu.eus. 11. Department of Biochemistry and Molecular Biology, University of the Basque Country, Barrio Sarriena, S/N, 48940, Leioa, Bizkaia, Spain. izortze.santin@ehu.eus.
Abstract
AIMS/HYPOTHESIS: The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved. METHODS: Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays. RESULTS: DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines. CONCLUSIONS/ INTERPRETATION: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI.
AIMS/HYPOTHESIS: The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved. METHODS: Functional studies based on silencing or overexpression of DEXI were performed in rat and humanpancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays. RESULTS:DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines. CONCLUSIONS/ INTERPRETATION: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI.
Entities:
Keywords:
DEXI; Inflammation; Pancreatic beta cell; Susceptibility gene; Type 1 diabetes; Type I IFNs; Viral infection
Authors: X Li; A T Hastie; G A Hawkins; W C Moore; E J Ampleford; J Milosevic; H Li; W W Busse; S C Erzurum; N Kaminski; S E Wenzel; D A Meyers; E R Bleecker Journal: Allergy Date: 2015-07-24 Impact factor: 13.146
Authors: M Sato; H Suemori; N Hata; M Asagiri; K Ogasawara; K Nakao; T Nakaya; M Katsuki; S Noguchi; N Tanaka; T Taniguchi Journal: Immunity Date: 2000-10 Impact factor: 31.745
Authors: X Huang; J Yuang; A Goddard; A Foulis; R F James; A Lernmark; R Pujol-Borrell; A Rabinovitch; N Somoza; T A Stewart Journal: Diabetes Date: 1995-06 Impact factor: 9.461
Authors: Laura Marroqui; Reinaldo Sousa Dos Santos; Tina Fløyel; Fabio A Grieco; Izortze Santin; Anne Op de Beeck; Lorella Marselli; Piero Marchetti; Flemming Pociot; Decio L Eizirik Journal: Diabetes Date: 2015-08-03 Impact factor: 9.461
Authors: Scott A Soleimanpour; Aditi Gupta; Marina Bakay; Alana M Ferrari; David N Groff; João Fadista; Lynn A Spruce; Jake A Kushner; Leif Groop; Steven H Seeholzer; Brett A Kaufman; Hakon Hakonarson; Doris A Stoffers Journal: Cell Date: 2014-06-19 Impact factor: 41.582
Authors: Lucy J Davison; Chris Wallace; Jason D Cooper; Nathan F Cope; Nicola K Wilson; Deborah J Smyth; Joanna M M Howson; Nada Saleh; Abdullah Al-Jeffery; Karen L Angus; Helen E Stevens; Sarah Nutland; Simon Duley; Richard M R Coulson; Neil M Walker; Oliver S Burren; Catherine M Rice; Francois Cambien; Tanja Zeller; Thomas Munzel; Karl Lackner; Stefan Blakenberg; Peter Fraser; Berthold Gottgens; John A Todd; Tony Attwood; Stephanie Belz; Peter Braund; François Cambien; Jason Cooper; Abi Crisp-Hihn; Patrick Diemert; Panos Deloukas; Nicola Foad; Jeanette Erdmann; Alison H Goodall; Jay Gracey; Emma Gray; Rhian G Williams; Susanne Heimerl; Christian Hengstenberg; Jennifer Jolley; Unni Krishnan; Heather Lloyd-Jones; Ingrid Lugauer; Per Lundmark; Seraya Maouche; Jasbir S Moore; David Muir; Elizabeth Murray; Chris P Nelson; Jessica Neudert; David Niblett; Karen O'Leary; Willem H Ouwehand; Helen Pollard; Angela Rankin; Catherine M Rice; Hendrik Sager; Nilesh J Samani; Jennifer Sambrook; Gerd Schmitz; Michael Scholz; Laura Schroeder; Heribert Schunkert; Ann-Christine Syvannen; Stefanie Tennstedt; Chris Wallace Journal: Hum Mol Genet Date: 2011-10-11 Impact factor: 6.150
Authors: Laura Marroqui; Miguel Lopes; Reinaldo S dos Santos; Fabio A Grieco; Merja Roivainen; Sarah J Richardson; Noel G Morgan; Anne Op de Beeck; Decio L Eizirik Journal: Elife Date: 2015-06-10 Impact factor: 8.140
Authors: Reinaldo Sousa Dos Santos; Regla María Medina-Gali; Ignacio Babiloni-Chust; Laura Marroqui; Angel Nadal Journal: Int J Mol Sci Date: 2022-05-01 Impact factor: 6.208
Authors: Leah C Kottyan; Michael P Trimarchi; Xiaoming Lu; Julie M Caldwell; Avery Maddox; Sreeja Parameswaran; Michael Lape; Rahul J D'Mello; Madeline Bonfield; Adina Ballaban; Vincent Mukkada; Philip E Putnam; Pablo Abonia; Netali Ben-Baruch Morgenstern; Amy A Eapen; Ting Wen; Matthew T Weirauch; Marc E Rothenberg Journal: J Allergy Clin Immunol Date: 2020-10-23 Impact factor: 14.290
Authors: Mireia Ramos-Rodríguez; Helena Raurell-Vila; Maikel L Colli; Maria Inês Alvelos; Marc Subirana-Granés; Jonàs Juan-Mateu; Richard Norris; Jean-Valery Turatsinze; Ernesto S Nakayasu; Bobbie-Jo M Webb-Robertson; Jamie R J Inshaw; Piero Marchetti; Lorenzo Piemonti; Manel Esteller; John A Todd; Thomas O Metz; Décio L Eizirik; Lorenzo Pasquali Journal: Nat Genet Date: 2019-11-01 Impact factor: 38.330