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Ubiquitin-Conjugating Enzyme Ubc13 Is a Critical Component of TNF Receptor-Associated Factor (TRAF)-Mediated Inflammatory Responses

Toru Fukushima, Shu-ichi Matsuzawa, Christina L. Kress, Jean Marie Bruey, Maryla Krajewska, Sophie Lefebvre, Juan M. Zapata, Ze'ev Ronai and John C. Reed
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 15 (Apr. 10, 2007), pp. 6371-6376
Stable URL: http://www.jstor.org/stable/25427384
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Ubiquitin-Conjugating Enzyme Ubc13 Is a Critical Component of TNF Receptor-Associated Factor (TRAF)-Mediated Inflammatory Responses
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Abstract

Ube 13 is a ubiquitin-conjugating enzyme responsible for noncanonical ubiquitination of TNF receptor-associated factor (TRAF)family adapter proteins involved in Toll-like receptor and TNFfamily cytokine receptor signaling, which are regulators of innate immunity. Gene ablation was used to study the function of Ubc13 in mice. Whereas homozygous ubc13 gene disruption resulted in embryonic lethality, heterozygous $ubc13^{+/-}$ mice appeared normal, without alterations in immune cell populations. Haploinsufficient $ubc13^{+/-}$ mice were resistant to lipopolysaccharide-induced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from $ubc13^{+/-}$ mice exhibited reduced lipopolysaccharide-inducible cytokine secretion and impaired activation of TRAF-dependent signal transduction pathways (NF-κB, JNK, and p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses and suggest that agents reducing Ubc13 activity could have therapeutic utility.

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