Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways
Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways
复制标题
钙调神经磷酸酶调节因子 1 (RCAN1) 的降解由伴侣介导的自噬和泛素蛋白酶体途径介导
DOI：
10.1096/fj.09-134296
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发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Sun, Xiulian
中科院分区：
文献类型：
--
作者：
Liu, Heng;Wang, Pin;Sun, Xiulian
钙调神经磷酸酶1(RCAN1)是一个发现于唐氏综合征关键区的基因，与阿尔茨海默病(AD)的发病机制有关。RCAN1基因在AD大鼠脑内表达增强，但其基因调控机制尚不清楚。本研究旨在探讨RCAN1蛋白降解的分子机制。除了通过泛素蛋白酶体途径降解外，我们发现溶酶体抑制以时间和剂量依赖的方式显著增加RCAN1蛋白的表达。抑制宏自噬减少了RCAN1的表达，表明RCAN1的降解不是通过宏自噬途径进行的。然而，破坏伴侣介导的自噬(CMA)增加了RCAN1的表达。在RCAN1蛋白中鉴定了两个CMA识别基序，通过CMA-溶酶体途径介导其降解。启动子分析进一步表明，抑制细胞中RCAN1的降解会降低钙调神经磷酸酶-NFAT的活性。泛素-蛋白酶体和自噬-溶酶体途径的功能障碍与神经退行性疾病有关。因此，阐明RCAN1通过泛素蛋白酶体途径和CMA-溶酶体途径的降解将极大地促进我们对AD发病机制的理解。FASE B J.23,3383-3392(2009)。Www.fasebj.org
Regulator of calcineurin 1 (RCAN1), a gene identified from the critical region of Down syndrome, has been implied in pathogenesis of Alzheimer's disease ( AD). RCAN1 expression was shown to be increased in AD brains; however, the mechanism of RCAN1 gene regulation is not well defined. The present study was designed to investigate the molecular mechanism of RCAN1 protein degradation. In addition to being degraded through the ubiquitin proteasome pathway, we found that lysosomal inhibition markedly increased RCAN1 protein expression in a time- and dosage-dependent manner. Inhibition of macroautophagy reduced RCAN1 expression, indicating that RCAN1 degradation is not through a macroautophagy pathway. However, disruption of chaperone-mediated autophagy (CMA) increased RCAN1 expression. Two CMA recognition motifs were indentified in RCAN1 protein to mediate its degradation through a CMA-lysosome pathway. A promoter assay further demonstrated that inhibition of RCAN1 degradation in cells reduced calcineurin-NFAT activity. Dysfunctions of ubiquitin-proteasome and autophagy-lysosome pathways have been implicated in neurodegenerative diseases. Therefore, elucidation of RCAN1 degradation by a ubiquitin proteasome pathway and CMA-lysosome pathway in the present study may greatly advance our understanding of AD pathogenesis.-Liu, H., Wang, P., Song, W., Sun, X. Degradation of regulator of calcineurin 1 ( RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J. 23, 3383-3392 ( 2009). www.fasebj.org