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Unbiased profiling of the human proinsulin biosynthetic interaction network reveals a role for peroxiredoxin 4 in proinsulin folding
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posted on 2020-05-29, 17:14 authored by Ada AdminAda Admin, Duc T. Tran, Anita Pottekat, Saiful A. Mir, Salvatore Loguercio, Insook Jang, Alexandre Rosa Campos, Kathleen M. Scully, Reyhaneh Lahmy, Ming Liu, Peter Arvan, William E. Balch, Randal J. Kaufman, Pamela Itkin-AnsariThe beta cell
protein synthetic machinery is dedicated to the production of mature insulin,
which requires the proper folding and trafficking of its precursor, proinsulin.
The complete network of proteins that mediate proinsulin folding and
advancement through the secretory pathway,
however, remains poorly defined. Here we used affinity purification and mass
spectrometry to identify for the first time, the proinsulin biosynthetic
interaction network in human islets. Stringent
analysis established a central node of proinsulin interactions with ER folding
factors, including chaperones and oxidoreductases, that is remarkably
conserved in both sexes and across three ethnicities. The
ER-localized peroxiredoxin PRDX4 was
identified as a prominent proinsulin interacting protein. In beta cells, gene
silencing of PRDX4 rendered proinsulin susceptible to misfolding, particularly
in response to oxidative stress, while exogenous PRDX4 improved proinsulin
folding. Moreover, proinsulin misfolding
induced by oxidative stress or high glucose was accompanied by sulfonylation of
PRDX4, a modification known to inactivate peroxiredoxins. Notably, islets from
patients with Type II diabetes (T2D) exhibited significantly higher levels of
sulfonylated PRDX4 than islets from healthy individuals. In conclusion, we have
generated the first reference map of the human
proinsulin interactome to identify critical factors
controlling insulin biosynthesis, beta cell function, and T2D.