Fukushima Toru, Matsuzawa Shu-ichi, Kress Christina L, Bruey Jean Marie, Krajewska Maryla, Lefebvre Sophie, Zapata Juan M, Ronai Ze'ev, Reed John C
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6371-6. doi: 10.1073/pnas.0700548104. Epub 2007 Apr 2.
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.
Ubc13是一种泛素结合酶，负责对参与Toll样受体和TNF家族细胞因子受体信号传导的TNF受体相关因子（TRAF）家族衔接蛋白进行非经典泛素化，这些信号传导是先天免疫的调节因子。基因敲除被用于研究Ubc13在小鼠中的功能。纯合ubc13基因破坏导致胚胎致死，而异合子ubc13(+/-)小鼠看起来正常，免疫细胞群体没有改变。ubc13(+/-)单倍体不足小鼠对脂多糖诱导的致死具有抗性，并显示TRAF6的体内泛素化减少。从ubc13(+/-)小鼠分离的巨噬细胞和脾细胞表现出脂多糖诱导的细胞因子分泌减少以及TRAF依赖性信号转导途径（NF-κB、JNK和p38 MAPK）的激活受损。这些发现证明了Ubc13在炎症反应中的关键作用，并表明降低Ubc13活性的药物可能具有治疗用途。
