期刊
EXPERIMENTAL CELL RESEARCH
卷 327, 期 1, 页码 48-56出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2014.05.013
关键词
AF1Q; Chaperone-mediated autophagy; Protein degradation; macroautophagy
资金
- National Nature Science Foundation of China [81070422, 30871088, 81200377]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, Ministry of Education) [20100131110060]
- Independent Innovation Fund of Shandong University [yzc12161]
- National Qianren Scholar Program Special Funding of Shandong University
- Taishan Scholar Special Funding of Shandong Province
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.
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