Found in Translation: Novel Insights Into Type 1 Diabetes and β-Cell Biology.

Abstract

Although essential features in the natural history of type 1 diabetes are generally understood (1), many key questions remain. In particular, despite decades of research, the precise events that cause immune tolerance mechanisms to fail, triggering autoimmunity, remain unclear (2). One theory that has attracted considerable recent attention is that β-cell “stress” can trigger or potentiate autoimmunity by generating neoantigens (3–5), for example, by posttranslational modifications, hybrid peptide formation, or protein splicing (6). In this issue, Thomaidou et al. (7) significantly expand our knowledge of two other potential sources of “neo-antigens,” namely, the products of translation from noncanonical start sites, and alternatively spliced transcripts. Using a combination of ribosomal profiling (8) and long read RNA sequencing, they show that β-cells can use at least 15,014 unique translation start sites within transcripts from the 5,529 genes whose expression they detected. Ribosome profiling was initially developed by Ingolia, Weissman, and colleagues (8) and is based on next-generation sequencing of the ∼30 base pairs fragments of mRNA that are protected from nuclease digestion by bound ribosomes. Combining this approach with pharmacological treatment to accumulate ribosomes at the sites of initiation allows accurate inference of translational reading frames. This powerful technique is now widely used to study many aspects of translation but had not previously been applied to human β-cells. Surprisingly, only 17% of the …