E2 Polyubiquitin-conjugating Enzyme Ubc13 in Keratinocytes Is Essential for Epidermal Integrity
E2 Polyubiquitin-conjugating Enzyme Ubc13 in Keratinocytes Is Essential for Epidermal Integrity
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DOI：
10.1074/jbc.m110.106484
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发表时间：
2010-09-24
影响因子：
4.8
通讯作者：
Hashimoto, Koji
中科院分区：
文献类型：
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作者：
Sayama, Koji;Yamamoto, Masahiro;Hashimoto, Koji
E2多泛素结合酶UBC13是一种天然免疫反应的介体。在核因子-kappaB活化过程中，UBC13介导角蛋白(K)63连接的多泛素链与肿瘤坏死因子受体相关因子6和IKK-γ的偶联。与K48连接的多泛素链不同，K63连接的多泛素链在非蛋白酶体的生物过程中发挥作用。尽管UBC13在Toll样受体(TLR)和IL-1受体信号转导中起关键作用，但UBC13在表皮中的功能尚未被研究。我们产生了角质形成细胞特异性的UBC13缺陷小鼠(UBC13(FLOX/FLOX)K5-CRE)。出生时，UBC13(FLOX/FLOX)K5-CRE小鼠的皮肤异常光亮光滑；此外，小鼠没有生长，出生后第2天死亡。组织学分析显示表皮萎缩，角质形成细胞凋亡。免疫组织化学分析显示UBC13(FLOX/FLOX)K5-CRE小鼠表皮角质形成细胞增殖减少、分化异常和凋亡。在培养中，UBC13(FLOX/FLOX)K5-Cre角质形成细胞生长受阻，细胞自发性死亡。此外，携带Cre重组酶的腺病毒载体从培养的UBC13(FLOX/FLOX)角质形成细胞中缺失UBC13也可导致细胞自发死亡。因此，UBC13对于角质形成细胞的生长、分化和存活是必不可少的。细胞内信号分析显示，在UBC13(FLOX/FLOX)K5-CRE角质形成细胞中，IL-1和TNF诱导的JNK、p38和NF-kappa B通路的激活受到损害。总之，UBC13似乎对小鼠的表皮完整性是必不可少的。
The E2 polyubiquitin-conjugating enzyme Ubc13 is a mediator of innate immune reactions. Ubc13 mediates the conjugation of keratin (K)63-linked polyubiquitin chains onto TNF receptor-associated factor 6 and IKK gamma during NF-kappa B activation. In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes. Although Ubc13 has been shown to be critical for Toll-like receptor (TLR) and IL-1 receptor signaling, the function of Ubc13 in the epidermis has not been studied. We generated keratinocyte-specific Ubc13-deficient mice (Ubc13(flox/flox)K5-Cre). At birth, the skin of the Ubc13(flox/flox)K5-Cre mice was abnormally shiny and smooth; in addition, the mice did not grow and died by postnatal day 2. Histological analysis showed atrophy of the epidermis with keratinocyte apoptosis. Immunohistochemical analyses revealed reduced proliferation, abnormal differentiation, and apoptosis of keratinocytes in the Ubc13(flox/flox)K5-Cre mouse epidermis. In culture, Ubc13(flox/flox)K5-Cre keratinocyte growth was impaired, and spontaneous cell death occurred. Moreover, the deletion of Ubc13 from cultured Ubc13(flox/flox) keratinocytes by means of an adenoviral vector carrying Cre recombinase also resulted in spontaneous cell death. Therefore, Ubc13 is essential for keratinocyte growth, differentiation, and survival. Analyses of intracellular signaling revealed that the IL-1 and TNF-induced activation of JNK, p38, and NF-kappa B pathways was impaired in Ubc13(flox/flox)K5-Cre keratinocytes. In conclusion, Ubc13 appears to be essential for epidermal integrity in mice.