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

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 resistantto lipopolysaccharicle-incluced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from ubc1(3+/-) mice exhibited reduced lipopolysaccharicle-inclucible cytokine secretion and impaired activation of TRAF-dependent signal transcluction pathways (NIF-kappa B, JNK, and p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses and suggestthat agents reducing Ubc13 activity could have therapeutic utility.