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Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells

par Szymczak, Florian ;Alvelos, Maria Inês;Marin Canas, Sandra ;Oliveira Castela, Angela Sofia ;Demine, Stéphane ;Colli, Maikel Luis ;Op De Beeck, Anne ;Thomaidou, Sofia;Marselli, L.;Zaldumbide, Arnaud AZ;Marchetti, Piero;Eizirik, Décio L
Référence Science advances, 8, 37, eabn5732
Publication Publié, 2022-09

Article révisé par les pairs

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Résumé :

IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα up-regulates HLA class I expression in human β cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNα induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation–related genes, and chemokines. NLRC5 also mediates the effects of IFNα on alternative splicing, a generator of β cell neoantigens, suggesting that it is a central player of the effects of IFNα on β cells that contribute to trigger and amplify autoimmunity in T1D.