Nuclear Ubiquitin Ligases, NF-κB Degradation, and the Control of Inflammation
Nuclear Ubiquitin Ligases, NF-κB Degradation, and the Control of Inflammation
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DOI：
10.1126/stke.11pe1
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发表时间：
2008-01-08
影响因子：
7.3
通讯作者：
Chiocca, Susanna
中科院分区：
文献类型：
--
作者：
Natoli, Gioacchino;Chiocca, Susanna
参与炎症反应的绝大多数基因的转录控制需要转录因子的核因子κ B（NF-κ B）家族。NF-κ B活性的刺激和终止受到严格的时空控制。根据NF-κ B调节的经典模型，激活和终止机制都集中于NF-κ B（I κ B）蛋白的抑制剂。而NF-κ B的活化需要I κ B的降解，负责终止NF-κ B活性的主要机制是特异性I κ B，I κ B α的再合成，其在细胞核中螯合NF-κ B二聚体并将它们以无活性形式易位到细胞质中。现在的研究表明，防止NF-κ B蛋白不受控制的活性所需的另一种机制是它们的核降解。已经鉴定了至少两种E3泛素连接酶，其中一种似乎是髓样细胞中控制核NF-κ B p65（也称为RelA）所必需的。此外，额外的证据表明，具有特定激活或抑制特性的单个NF-κ B二聚体可能受到核降解的差异控制，从而为利用NF-κ B降解途径用于治疗目的铺平了道路。
Transcriptional control of the vast majority of genes involved in the inflammatory response requires the nuclear factor kappa B (NF-kappa B) family of transcription factors. Stimulation and termination of NF-kappa B activity are subject to stringent spatiotemporal control. According to the classical model of NF-kappa B regulation, both activation and termination mechanisms are centered on inhibitor of NF-kappa B (I kappa B) proteins. Whereas activation of NF-kappa B requires degradation of the I kappa Bs, the main mechanism responsible for termination of NF-kappa B activity is the resynthesis of a specific I kappa B, I kappa B alpha, which sequesters NF-kappa B dimers in the nucleus and translocates them to the cytoplasm in an inactive form. Studies now show that an additional mechanism that is required to prevent the uncontrolled activity of NF-kappa B proteins is their nuclear degradation. At least two E3 ubiquitin ligases, one of which seems to be essential for control of nuclear NF-kappa B p65 (also known as RelA) in myeloid cells, have been identified. Moreover, additional evidence indicates that individual NF-kappa B dimers with particular activating or repressive properties may be differentially controlled by nuclear degradation, thus paving the way for the exploitation of NF-kappa B degradation pathways for the rapeutic purposes.