Degradation of AF1Q by chaperone-mediated autophagy
Degradation of AF1Q by chaperone-mediated autophagy
复制标题
分子伴侣介导的自噬降解 AF1Q
DOI：
10.1016/j.yexcr.2014.05.013
复制
发表时间：
2014-09-10
影响因子：
3.7
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Li, Peng;Ji, Min;Ji, Chunyan
AF 1 Q是一种混合系白血病基因融合伴侣，被鉴定为儿童急性髓细胞白血病（AML）、细胞遗传学正常的成人AML和成人骨髓增生异常综合征的预后不良生物标志物。AF 1 Q在造血祖细胞分化发育过程中受到高度调控，但其调控机制尚不清楚。本研究从药理学和遗传学两个方面对分子伴侣介导的自噬进行了研究，并探讨了AF 1 Q的降解机制。溶酶体降解的药理学抑制剂，如氯喹，增加AF 1 Q水平，而CMA的激活剂，包括6-氨基烟酰胺和营养饥饿，降低AF 1 Q水平。AF 1 Q与HSPA 8和LAMP-2A相互作用，这是CMA机制的核心组成部分。HSPA 8或LAMP-2A的敲低增加AF 1 Q蛋白水平，而过表达显示相反的效果。使用氨基酸缺失AF 1 Q突变质粒，我们确定AF 1 Q具有KFERQ样基序，该基序被HSPA 8识别为CMA依赖的蛋白水解。总之，我们第一次证明，AF 1 Q可以在溶酶体中被CMA降解。(C)2014爱思唯尔公司All rights reserved.
AF1Q, a mixed lineage leukemia gene fusion partner, is identified as a poor prognostic biomarker for pediatric acute myeloid leukemia (AML), adult AML with normal cytogenetic and adult myelodysplastic syndrome. AF1Q is highly regulated during hematopoietic progenitor differentiation and development but its regulatory mechanism has not been defined clearly. In the present study, we used pharmacological and genetic approaches to influence chaperone-mediated autophagy (CMA) and explored the degradation mechanism of AF1Q. Pharmacological inhibitors of lysosomal degradation, such as chloroquine, increased AF1Q levels, whereas activators of CMA, including 6-aminonicotinamide and nutrient starvation, decreased AF1Q levels. AF1Q interacts with HSPA8 and LAMP-2A, which are core components of the CMA machinery. Knockdown of HSPA8 or LAMP-2A increased AF1Q protein levels, whereas overexpression showed the opposite effect. Using an amino acid deletion AF1Q mutation plasmid, we identified that AF1Q had a KFERQ-like motif which was recognized by HSPA8 for CMA-dependent proteolysis. In conclusion, we demonstrate for the first time that AF1Q can be degraded in lysosomes by CMA. (C) 2014 Elsevier Inc. All rights reserved.