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

Sci Adv. 2022 Sep 16;8(37):eabn5732. doi: 10.1126/sciadv.abn5732. Epub 2022 Sep 14.

Abstract

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.

MeSH terms

  • Alternative Splicing
  • Diabetes Mellitus, Type 1* / genetics
  • Diabetes Mellitus, Type 1* / metabolism
  • Humans
  • Insulin-Secreting Cells*
  • Interferon-alpha / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Islets of Langerhans* / metabolism
  • Transcription, Genetic

Substances

  • Interferon-alpha
  • Intracellular Signaling Peptides and Proteins
  • NLRC5 protein, human