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Long RNA Sequencing and Ribosome Profiling of Inflamed β-Cells Reveal an Extensive Translatome Landscape

2021; American Diabetes Association; Volume: 70; Issue: 10 Linguagem: Inglês

10.2337/db20-1122

1939-327X

Sofia Thomaidou, Roderick C. Slieker, Arno R. van der Slik, J. H. VAN BOOM, Flip Mulder, Amadeo Muñoz García, Leen M. ‘t Hart, Bobby P. C. Koeleman, Françoise Carlotti, Rob C. Hoeben, Bart O. Roep, Hailiang Mei, Arnaud Zaldumbide,

Immune Cell Function and Interaction

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell–mediated destruction of the insulin-producing pancreatic β-cells. Increasing evidence suggest that the β-cells themselves contribute to their own destruction by generating neoantigens through the production of aberrant or modified proteins that escape central tolerance. We recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human β-cells, emphasizing the participation of nonconventional translation events in autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human β-cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from noncanonical start sites and translation initiation within long noncoding RNA. Our data underline the extreme diversity of the β-cell translatome and may reveal new functional biomarkers for β-cell distress, disease prediction and progression, and therapeutic intervention in T1D.