Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 63,046 bioRxiv papers from 279,617 authors.

A reference map of the human proinsulin biosynthetic interaction network

By Duc T Tran, Anita Pottekat, Saiful A Mir, Insook Jang, Salvatore Loguercio, Alexandre Rosa Campos, Reyhaneh Lahmy, Ming Liu, Peter Arvan, William E Balch, Randal J. Kaufman, Pamela Itkin-Ansari

Posted 11 Jul 2019
bioRxiv DOI: 10.1101/699132

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.

Download data

  • Downloaded 164 times
  • Download rankings, all-time:
    • Site-wide: 48,856 out of 63,046
    • In biochemistry: 1,403 out of 1,823
  • Year to date:
    • Site-wide: 25,449 out of 63,046
  • Since beginning of last month:
    • Site-wide: 13,623 out of 63,046

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide

Sign up for the Rxivist weekly newsletter! (Click here for more details.)