Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

doi:10.1073/pnas.0700548104

Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved February 16, 2007 (received for review January 19, 2007)

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-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.

Footnotes

*To whom correspondence should be addressed. E-mail: reedoffice{at}burnham.org
Author contributions: T.F and S.-i.M. contributed equally to this work; S.-i.M., Z.R., and J.C.R. designed research; T.F., S.-i.M., C.L.K., J.M.B., M.K., S.L., and J.M.Z. performed research; T.F., S.-i.M., J.M.Z., Z.R., and J.C.R. analyzed data; and S.-i.M., Z.R., and J.C.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700548104/DC1.
Abbreviations:

γTriDAP,

H-Ala-d-γ-Glu-diaminopimelic acid;

LPS,

lipopolysaccharide;

TLR,

Toll-like receptor;

TNFR,

TNF receptor;

TRAF,

TNFR-associated factor.