title: Degradation of AF1Q by chaperone-mediated autophagy.
abstract: 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.
authors.affiliation: Department of Hematology, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hematology, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Hematology, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Hematology, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Li
authors.affiliation: Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
authors.affiliation: Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li Wang
authors.affiliation: Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China; Center for Stem Cell & Regenerative Medicine, The Second Hospital of Shandong University, Jinan 250033, P.R. China. Electronic address: tangdq@sdu.edu.cn.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Hematology, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, P.R. China. Electronic address: jichunyan@sdu.edu.cn.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology; D000595:Amino Acid Sequence; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; C091736:MLLT11 protein, human; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D015120:6-Aminonicotinamide; D002738:Chloroquine
keywords: AF1Q; Chaperone-mediated autophagy; Protein degradation; macroautophagy