Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical ubiquitination of TRAF-family adapter proteins involved in Toll-like Receptor (TLR) and TNF-family cytokine receptor signaling. Gene ablation was used to study the function of Ubc13 in mice. While 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 (LPS)-induced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from ubc13+/− mice exhibited reduced LPS-inducible cytokine secretion and impaired activation of TRAF-dependent signal transduction pathways (NF-kB, JNK, p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses, and suggest that agents reducing Ubc13 activity could have therapeutic utility.

Topics:
enzymes, inflammatory response, ubiquitin, ablation, cytokine, lipopolysaccharides, mitogen-activated protein kinase p38, nf-kappa b, receptors, cytokine, toll-like receptor

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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