SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling
SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling
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DOI：
10.1016/j.immuni.2005.04.008
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发表时间：
2005-06-01
期刊：
影响因子：
32.4
通讯作者：
Grusby, MJ
中科院分区：
文献类型：
--
作者：
Tanaka, T;Soriano, MA;Grusby, MJ
STAT蛋白是一个潜伏的细胞质转录因子家族，其响应于多种细胞因子、生长因子和激素而被酪氨酸磷酸化激活。一旦激活，STAT蛋白质易位到细胞核中，并帮助协调基因转录。STAT信号传导的一个显著特征是其快速和短暂的激活和失活循环，尽管对此负责的分子机制仍然知之甚少。在这里，我们报告的核蛋白，包含PDZ和LIM结构域，并与激活的STAT4分子相互作用。我们发现SLIM是一种泛素E3连接酶，作用于STAT蛋白，导致其蛋白体介导的降解，并增强其去磷酸化。SLIM的过表达由于STAT蛋白水平降低而导致STAT 1和STAT 4活性受损，而SLIM缺乏导致STAT表达增加，从而增强Th1细胞的IFN γ产生。这些研究表明，SLIM是一种新的泛素E3连接酶，其靶点包括STAT蛋白。
STAT proteins are a family of latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation in response to a variety of cytokines, growth factors, and hormones. Once activated, STAT proteins translocate into the nucleus and help coordinate gene transcription. One striking feature of STAT signaling is its rapid and transient activation and deactivation cycle, although the molecular mechanisms responsible for this remain poorly understood. Here, we report on a nuclear protein that contains both PDZ and LIM domains and that interacts with activated STAT4 molecules. We show that SLIM is an ubiquitin E3 ligase that acts on STAT proteins to cause their proteosome-mediated degradation and enhance their dephosphorylation. Overexpression of SLIM leads to impaired STAT1 and STAT4 activity due to reduced STAT protein levels, while SLIM-deficiency results in increased STAT expression and thus enhanced IFN gamma production by Th1 cells. These studies suggest that SLIM is a novel ubiquitin E3 ligase whose targets include STAT proteins.