Editors' ChoiceDiabetes

What’s Hypusine Got to Do with Diabetes? Well, Maybe a Lot!

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Science Translational Medicine  09 Jun 2010:
Vol. 2, Issue 35, pp. 35ec90
DOI: 10.1126/scitranslmed.3001330

Hypusine [Nε-(4-amino-2-hydroxybutyl)-lysine] is an unusual amino acid found in all eukaryotes. In humans, the eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein known to contain hypusine, formed posttranslationally by hypusination of the ε-NH2 group of Lys50 in the inactive eIF5A protein. Although eIF5A affects processes such as cellular proliferation and apoptosis, recent data suggest a role for the protein in inflammatory responses as well. Since eIF5A is found in pancreatic β cells, where it facilitates the production of proinflammatory cytokines that can contribute to islet cell dysfunction in both type 1 (autoimmune) diabetes and type 2 (insulin resistance–associated) diabetes, Maier et al. examined the role of eIF5A in the pathogenesis of these two common conditions.

By using inflammatory mouse models of diabetes—C57BL/6J mice (with an intact immune system) and NOD/SCID/Il2rg–null mice (without innate or adaptive immune systems)—the authors found that depletion of eIF5A with small intering RNA molecules or inhibition of eIF5A hypusination protected the animals against glucose intolerance, cytokine-induced islet dysfunction, and islet cell loss. Furthermore, they showed that eIF5A regulated inducible nitric oxide synthase (iNOS) production and that eIF5A depletion in both rodent β cells and human islets led to the impaired translation of iNOS-encoding mRNA. The hypusination of eIF5A was necessary for the nuclear export of iNOS-encoding mRNA, a process requiring the presence of the export protein exoportin1.

Taken together, these findings—from experiments studying mouse and human islet cell function—suggest that the amino acid hypusine in eIF5A and the hypusinating enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase may present therapeutic targets for the prevention of cytokine-induced inflammation and islet cell dysfunction in both types 1 and 2 diabetes, disorders that afflict over 200 million people worldwide.

B. Maier et al., The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice. J. Clin. Investig. 120, 2156–2170 (2010). [Full Text]

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