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

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