The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice

Bernhard Maier, Takeshi Ogihara, Anthony P. Trace, Sarah A. Tersey, Reiesha D. Robbins, Swarup K. Chakrabarti, Craig S. Nunemaker, Natalie D. Stull, Catherine A. Taylor, John E. Thompson, Richard S. Dondero, Eli C. Lewis, Charles A. Dinarello, Jerry L. Nadler, Raghu Mirmira

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Abstract

In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to β cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent β cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.

Original languageEnglish
Pages (from-to)2156-2170
Number of pages15
JournalJournal of Clinical Investigation
Volume120
Issue number6
DOIs
StatePublished - Jun 1 2010

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Islets of Langerhans
Inflammation
Glucose Intolerance
Experimental Diabetes Mellitus
Messenger RNA
Cytokines
Cell Nucleus Active Transport
hypusine
eukaryotic translation initiation factor 5A
Type 1 Diabetes Mellitus
Hyperglycemia
Type 2 Diabetes Mellitus
Rodentia
Proteins
Amino Acids

ASJC Scopus subject areas

  • Medicine(all)

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The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice. / Maier, Bernhard; Ogihara, Takeshi; Trace, Anthony P.; Tersey, Sarah A.; Robbins, Reiesha D.; Chakrabarti, Swarup K.; Nunemaker, Craig S.; Stull, Natalie D.; Taylor, Catherine A.; Thompson, John E.; Dondero, Richard S.; Lewis, Eli C.; Dinarello, Charles A.; Nadler, Jerry L.; Mirmira, Raghu.

In: Journal of Clinical Investigation, Vol. 120, No. 6, 01.06.2010, p. 2156-2170.

Research output: Contribution to journalArticle

Maier, B, Ogihara, T, Trace, AP, Tersey, SA, Robbins, RD, Chakrabarti, SK, Nunemaker, CS, Stull, ND, Taylor, CA, Thompson, JE, Dondero, RS, Lewis, EC, Dinarello, CA, Nadler, JL & Mirmira, R 2010, 'The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice', Journal of Clinical Investigation, vol. 120, no. 6, pp. 2156-2170. https://doi.org/10.1172/JCI38924
Maier, Bernhard ; Ogihara, Takeshi ; Trace, Anthony P. ; Tersey, Sarah A. ; Robbins, Reiesha D. ; Chakrabarti, Swarup K. ; Nunemaker, Craig S. ; Stull, Natalie D. ; Taylor, Catherine A. ; Thompson, John E. ; Dondero, Richard S. ; Lewis, Eli C. ; Dinarello, Charles A. ; Nadler, Jerry L. ; Mirmira, Raghu. / The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 6. pp. 2156-2170.
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AU - Robbins, Reiesha D.

AU - Chakrabarti, Swarup K.

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AU - Stull, Natalie D.

AU - Taylor, Catherine A.

AU - Thompson, John E.

AU - Dondero, Richard S.

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AU - Dinarello, Charles A.

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