Inflammatory cytokines rewire the proinsulin interaction in human islets
Date
2022
Authors
Tran, D.T.
Pottekat, A.
Lee, K.
Raghunathan, M.
Loguercio, S.
Mir, S.A.
Paton, A.W.
Paton, J.C.
Arvan, P.
Kaufman, R.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2022; 107(11):3100-3110
Statement of Responsibility
Duc T. Tran, Anita Pottekat, Kouta Lee, Megha Raghunathan, Salvatore Loguercio, Saiful A. Mir, Adrienne W. Paton, James C. Paton, Peter Arvan, Randal J. Kaufman, and Pamela Itkin-Ansari
Conference Name
Abstract
CONTEXT: Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both Type I and Type II diabetes (T1D, T2D). Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes but the mechanisms remain unclear. OBJECTIVE: We sought to determine the effect of the diabetes associated cytokines on proinsulin folding, trafficking, secretion, and b-cell function. DESIGN: Human islets were treated with interleukin-1β and interferon-γ for forty-eight hours, followed by analysis of IL6, nitrite, proinsulin and insulin release, RNAseq, and unbiased profiling of the proinsulin interactome by Affinity Purification-Mass Spectrometry (AP-MS). RESULTS: Cytokine treatment induced secretion of IL6, nitrites, and insulin, as well as aberrant release of proinsulin. RNAseq showed that cytokines upregulated genes involved in ER stress and consistent with this, AP-MS revealed cytokine induced proinsulin binding to multiple ER chaperones and oxidoreductases. Moreover, increased binding to the chaperone BiP was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and T1D and T2D GWAS candidate proteins not previously known to interact with proinsulin (e.g., Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion. CONCLUSION: Together, the data shed new light on mechanisms by which diabetes associated cytokines dysregulate β-cell function. For the first time we show that even short term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.
School/Discipline
Dissertation Note
Provenance
Description
Corrected by: Correction to “Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets”, The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 4, 1 April 2023, Page e61, https://doi.org/10.1210/clinem/dgac713, an error occurred in the Correspondence section: The Correspondence section listed one corresponding author: “Pamela Itkin-Ansari, PhD, Adjunct, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Email: pitkin@sbpdiscovery.org.” The article should state that author Randal J. Kaufman is a co-corresponding author. The corrected Correspondence section is: “Randal J. Kaufman, PhD, Sandford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Email: rkaufman@sbpdiscovery.org or Pamela Itkin-Ansari, PhD, Adjunct, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Email: pitkin@ sbpdiscovery.org.” The article has been corrected online. doi.org/10.1210/clinem/dgac493
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Rights
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.