Ubiquitin-specific protease 14 regulates LPS-induced inflammation by increasing ERK1/2 phosphorylation and NF-κB activation
Ubiquitin-specific protease 14 regulates LPS-induced inflammation by increasing ERK1/2 phosphorylation and NF-κB activation
复制标题
泛素特异性蛋白酶 14 通过增加 ERK1/2 磷酸化和 NF-κ B 激活来调节 LPS 诱导的炎症
DOI：
10.1007/s11010-017-2978-0
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发表时间：
2017-07-01
影响因子：
4.3
通讯作者：
Zhang, Zhenhui
中科院分区：
文献类型：
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作者：
Liu, Ningning;Kong, Tianyu;Zhang, Zhenhui
核因子B（NF-κ B）的持续活化在调节巨噬细胞对微生物感染的细胞应答中是非常重要的。去泛素化酶USP14对泛素介导的蛋白质降解至关重要，已知与癌症、神经系统疾病和衰老有关。然而，USP14调节炎症的机制仍不清楚。在这里，我们证明了降低USP 14的去泛素化酶活性导致THP-1和RAW 264.7细胞中脂多糖（LPS）介导的肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6释放减少。同时，通过SiRNA敲除USP 14也表现出同样的效果，并且对THP-1细胞没有细胞毒性。此外，抑制USP 14或USP 14敲低的去泛素化酶活性导致ERK 1/2和I κ B α磷酸化降低，NF-κ B抑制剂I κ B α的量增加，以及NF-κ B p65从细胞质向细胞核的转运减少。这些发现表明USP 14诱导由微生物感染触发的NF-κ B活性和ERK 1/2磷酸化。
Persistent activation of nuclear factor B (NF-kappa B) is very important in the modulation of macrophages cellular response to microbial infections. The deubiquitinase USP14, which is critical for ubiquitin-mediated proteasomal degradation of proteins, is known to be involved in cancer, neurological diseases, and aging. However, the mechanism by which USP14 regulates inflammation remains unclear. Here, we demonstrated that decreasing the deubiquitinase activity of USP14 resulted in reduced lipopolysaccharides (LPS)-mediated tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 release in THP-1 and RAW264.7 cells. Meanwhile, USP14 knockdown by siRNA showed the same effects, with no cytotoxicity in THP-1 cells. Moreover, inhibiting the deubiquitinase activity of USP14 or USP14 knockdown resulted in decreased ERK1/2 and I kappa B alpha phosphorylation, increased amounts of the NF-kappa B inhibitor I kappa B alpha, and reduced NF-kappa B p65 transport from the cytoplasm into nucleus. These findings suggested that USP14 induces NF-kappa B activity and ERK1/2 phosphorylation triggered by microbial infection.