The fusion oncoprotein PML-RARα induces endoplasmic reticulum (ER)-associated degradation of N-CoR and ER stress
The fusion oncoprotein PML-RARα induces endoplasmic reticulum (ER)-associated degradation of N-CoR and ER stress
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DOI：
10.1074/jbc.m312121200
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发表时间：
2004-03-19
影响因子：
4.8
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Khan, MM;Nomura, T;Ishii, S
PML-RAR α是早幼粒细胞白血病（PML）和视黄酸受体-α（RAR α）的融合蛋白，可引起急性早幼粒细胞白血病（APL）。尽管核PML-RAR α的作用已被广泛研究，但大量PML-RAR α存在于细胞质中。细胞质PML-RAR α在白血病发生中的作用尚不清楚。在这里，我们报告PML-RAR α诱导内质网（ER）中的N-CoR积累，导致ER应激的诱导和激活转录因子6（ATF 6）的加工，未折叠的蛋白质反应。PML-RAR alpha通过Ubc 6刺激N-CoR的泛素化，参与蛋白质质量控制。N-CoR的这种ER相关降解（ERAD）降低了细胞核中可溶性NCoR蛋白的水平。N-CoR的ERAD需要PML-RAR α中的两个N-CoR相互作用位点，这表明PML-RAR α与N-CoR的异常结合可能诱导N-CoR的ERAD。N-CoR的过表达诱导APL衍生的NB 4细胞的分化，表明核中的低水平N-CoR可能至少部分地有助于PML-RAR α介导的白血病发生。
PML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha), causes acute promyelocytic leukemias (APL). Although the role of nuclear PML-RARalpha has been extensively studied, a significant amount of PML-RARalpha is in the cytoplasm. The role cytoplasmic PML-RARalpha plays in leukemogenesis is unknown. Here we report that PML-RARalpha induces the N-CoR accumulation in the endoplasmic reticulum ( ER), leading to the induction of ER stress and the processing of activating transcription factor 6 (ATF6), the unfolded protein response. PML-RARalpha stimulates the ubiquitylation of N-CoR via Ubc6 that is involved in the protein quality control. This ER-associated degradation (ERAD) of N-CoR reduces the soluble NCoR protein levels in the nucleus. The two N-CoR-interacting sites in PML-RARalpha are required for the ERAD of N-CoR, suggesting the aberrant binding of PML-RARalpha to N-CoR may induce the ERAD of N-CoR. Overexpression of N-CoR induces the differentiation of APL-derived NB4 cells, suggesting that the low levels of N-CoR in the nucleus may contribute at least partly to PML-RARalpha mediated leukemogenesis.