title: Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses.
abstract: Ubc13 is a ubiquitin-conjugating enzyme responsible for noncanonical ubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in Toll-like receptor and TNF-family 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-kappaB, 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.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Fukushima
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kress
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Bruey
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Sophie
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zapata
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005434:Flow Cytometry; D006579:Heterozygote; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*
chemical_list: D048029:TNF Receptor-Associated Factor 6; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes