title: Bcl-2 Decreases the Affinity of SQSTM1/p62 to Poly-Ubiquitin Chains and Suppresses the Aggregation of Misfolded Protein in Neurodegenerative Disease.
abstract: Poly-ubiquitinated protein aggregate formation is the most striking hallmark of various neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Mutations of many ubiquitin-associated proteins involved in the regulation of protein aggregation, such as SQSTM1/p62 (p62), parkin, and VCP, are closely linked to neurodegeneration. B-cell lymphoma 2 (Bcl-2) is a key regulator in autophagy, apoptosis, and mitochondria quality control in many cell types including neurons, and it plays important roles in the pathogenesis of neurodegenerative diseases mentioned above. Our previous work showed that Bcl-2 can directly bind to p62, and here we report that Bcl-2 directly interacts with the N-terminus of p62, but not the C-terminus (UBA domain). Interestingly and importantly, Bcl-2 affects the affinity of p62 to poly-ubiquitin chains and suppresses the aggregation of poly-ubiquitinated proteins such as mutant huntingtin associated with Huntington's disease. Our study reveals a role of Bcl-2 that involves in the regulation of misfolded proteins.
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China.|Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui, 230027, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China.
authors.forename: Haigang
authors.initials: H
authors.lastname: Ren
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China. zheng.ying@suda.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ying
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China. wanggh@suda.edu.cn.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D019254:Genes, bcl-2; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D017510:Protein Folding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D057165:Proteostasis Deficiencies; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000071456:Sequestosome-1 Protein; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025821:Polyubiquitin
keywords: Aggregate; Bcl-2; Huntingtin; Neurodegenerative disease; SQSTM1/p62