van Veelen, P. | bioRxiv Science

bioRxiv2023

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic {beta}-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic {beta}-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of {beta}-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation. These results indicate that insulin-derived peptides, presented by HLA-class I molecules at the cell surface, originate from ER-resident proinsulin that has been dislocated to the cytosol for subsequent degradation. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future therapies that may cure or even prevent T1D. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/545333v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@131d5org.highwire.dtl.DTLVardef@6eb4b3org.highwire.dtl.DTLVardef@196674org.highwire.dtl.DTLVardef@1957af6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Neo-sex chromosomes and demography shape genetic diversity in the Critically Endangered Raso lark

Small effective population sizes could expose island species to inbreeding and loss of genetic variation. Here we investigate factors shaping genetic diversity in the Raso lark, which has been restricted to a single islet for ~500 years, with a population size of a few hundred. We assembled a reference genome for the related Eurasian skylark and then assessed diversity and demographic history using RAD-seq data (75 samples from Raso larks and two related mainland species). We first identify broad tracts of suppressed recombination in females, indicating enlarged neo-sex chromosomes. It is plausible that these regions might inadvertently and temporarily preserve pre-existing allelic variation in females that would otherwise be lost through genetic drift. We then show that genetic diversity across autosomes in the Raso lark is lower than in its mainland relatives, but inconsistent with long-term persistence at its current population size. Finally, we find that genetic signatures of the recent population contraction are overshadowed by an ancient expansion and persistence of a very large population until the human settlement of Cape Verde. Our findings show how genome-wide approaches to study endangered species can help avoid confounding effects of genome architecture on diversity estimates, and how present day diversity can be shaped by ancient demographic events.

genomics↗