The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription.
The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription.
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DOI：
10.1016/j.molcel.2012.03.007
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发表时间：
2012-05-11
期刊：
影响因子：
16
通讯作者：
Zhou, Qiang
中科院分区：
文献类型：
--
作者：
Liu, Min;Hsu, Joanne;Chan, Caleb;Li, Zichong;Zhou, Qiang
超延伸复合物（SEC）包含两种不同的转录延伸因子，P-TEFb和ELL 1/2，由支架蛋白AFF 4或AFF 1连接。它们刺激正常和疾病相关基因的表达，特别是HIV或参与白血病发生的基因。在所有SEC亚基中，ELL 2是化学计量限制性的，并且在蛋白质稳定性水平上被独特地调节。在这里，我们确定的RING结构域蛋白Siah 1，但不是同源Siah 2，作为E3泛素连接酶的ELL 2聚泛素化和蛋白酶体降解。Siah 1不能接近和泛素化与AFF 4结合的ELL 2，尽管在高浓度下，它也降解AFF 4/1以破坏SEC。Prostratin和HMBA是两种被充分研究的HIV转录和潜伏期激活剂，它们通过降低Siah 1表达和ELL 2多聚泛素化来增强ELL 2积累和SEC形成。鉴于其在SEC形成中的重要性，Siah 1泛素化途径为开发控制疾病相关转录的策略提供了新的途径。
Super Elongation Complexes (SECs) contain two different transcription elongation factors, P-TEFb and ELL1/2, linked by the scaffolding protein AFF4 or AFF1. They stimulate the expression of both normal and disease-related genes, especially those of HIV or involved in leukemogenesis. Among all SECs subunits, ELL2 is stoichiometrically limiting and uniquely regulated at the level of protein stability. Here we identify the RING domain protein Siah1, but not the homologous Siah2, as the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation. Siah1 cannot access and ubiquitinate ELL2 bound to AFF4, although at high concentrations, it also degrades AFF4/1 to destroy SECs. Prostratin and HMBA, two well-studied activators of HIV transcription and latency, enhance ELL2 accumulation and SECs formation largely through decreasing Siah1 expression and ELL2 polyubiquitination. Given its importance in formation of SECs, the Siah1 ubiquitination pathway provides a fresh avenue for developing strategies to control disease-related transcription.
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