Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,506 bioRxiv papers from 264,779 authors.
A reference map of the human proinsulin biosynthetic interaction network
Duc T Tran,
Saiful A Mir,
Alexandre Rosa Campos,
William E Balch,
Randal J. Kaufman,
Posted 11 Jul 2019
bioRxiv DOI: 10.1101/699132
Posted 11 Jul 2019
The beta-cell secretory protein synthetic machinery is dedicated to insulin production, and recent reports suggest that both proinsulin misfolding and accompanying beta-cell oxidative stress could be common features in type 2 diabetes (T2D). Despite the critical role of insulin in organismal homeostasis, the precise network of interactions from early proinsulin synthesis and folding in the ER, to its subsequent trafficking through the secretory pathway, remain poorly defined. In the present study we utilized a human proinsulin-specific monoclonal antibody for affinity purification mass spectrometry, to yield unbiased profiling of the proinsulin interactome in human islets. The data reveal that human proinsulin interacts with a network of ER folding factors (including chaperones: e.g. ERDJ5, ERDJ3, GRP94, and BiP; and oxidoreductases: e.g. QSOX1, DUOX2, and PRDX4) that are remarkably conserved across both genders and 3 ethnicities. Knockdown of one of the most prominent hits, peroxiredoxin-4 (PRDX4) in MIN6 beta-cells, rendered proinsulin more susceptible to misfolding. Additionally, oxidant exposure in human islets enhanced proinsulin:BiP interactions with augmented proinsulin misfolding. Finally, oxidant exposure in human islets also led to sulfonylation of PRDX4, a modification known to inactivate peroxiredoxins. Interestingly, we observed significantly higher levels of sulfonylated (inactive) PRDX4 in islets from patients with T2D compared to that of normal islets. Taken together, these data provide a detailed reference map of the human proinsulin interaction network and suggest critical unrecognized areas for study in insulin biosynthesis, beta cell function, and T2D.
- Downloaded 116 times
- Download rankings, all-time:
- Site-wide: 50,465 out of 57,506
- In biochemistry: 1,426 out of 1,642
- Year to date:
- Site-wide: 28,277 out of 57,506
- Since beginning of last month:
- Site-wide: 2,913 out of 57,506
Downloads over time
Distribution of downloads per paper, site-wide
- Top preprints of 2018
- Paper search
- Author leaderboards
- Overall metrics
- The API
- Email newsletter
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!