Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses
Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses
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DOI：
10.1073/pnas.0700548104
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发表时间：
2007-04-10
影响因子：
11.1
通讯作者：
Reed, John C.
中科院分区：
文献类型：
--
作者：
Fukushima, Toru;Matsuzawa, Shu-ichi;Reed, John C.
Ubc13 是一种泛素结合酶，负责 TNF 受体相关因子 (TRAF) 家族衔接蛋白的非经典泛素化，该衔接蛋白参与 Toll 样受体和 TNF 家族细胞因子受体信号传导，这些信号是先天免疫的调节因子。基因消融用于研究 Ubc13 在小鼠中的功能。纯合子 ubc13 基因破坏会导致胚胎死亡，而杂合子 ubc13(+/-) 小鼠则表现正常，免疫细胞群没有改变。单倍体不足的 ubc13(+/-) 小鼠对脂多糖致死具有抵抗力，并证明 TRAF6 体内泛素化减少。从 ubc1(3+/-) 小鼠中分离的巨噬细胞和脾细胞表现出脂多糖不溶性细胞因子分泌减少和 TRAF 依赖性信号转导途径（NIF-kappa B、JNK 和 p38 MAPK）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效用。
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.