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

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posted on 15.06.2021, 22:58 by Sofia Thomaidou, Roderick C. Slieker, Arno R. van der Slik, Jasper Boom, Flip Mulder, Amadeo Munoz-Garcia, Leen M. ‘t Hart, Bobby Koeleman, Francoise Carlotti, Rob C. Hoeben, Bart O. Roep, Hailiang Mei, Arnaud Zaldumbide
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.

Funding

This work is supported by JDRF, DON and the Dutch Diabetes Research Foundation and by the IMI2-JU under grant agreement No 115797 (INNODIA) and No 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and “EFPIA”, ‘JDRF” and “The Leona M. and Harry B. Helmsley Charitable Trust”. BOR is supported by the Wanek Family Project for Type 1 Diabetes.

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