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: Liang Zhou, Hongfeng Wang, Haigang Ren, Qingsong Hu, Zheng Ying, Guanghui Wang
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 52 Issue 3 Pg. 1180-1189 (Dec 2015) ISSN: 1559-1182 [Electronic] United States
• PMID: 25311206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• HTT protein, human
• Huntingtin Protein
• Nerve Tissue Proteins
• Peptide Fragments
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• SQSTM1 protein, human
• Sequestosome-1 Protein
• Polyubiquitin

Topics

• Adaptor Proteins, Signal Transducing (chemistry, metabolism)
• Cell Line, Tumor
• Genes, bcl-2
• HEK293 Cells
• Humans
• Huntingtin Protein
• Nerve Tissue Proteins (chemistry, genetics, metabolism)
• Neurodegenerative Diseases (metabolism)
• Peptide Fragments (metabolism)
• Polyubiquitin (metabolism)
• Protein Aggregation, Pathological
• Protein Binding
• Protein Folding
• Protein Interaction Mapping
• Protein Multimerization
• Protein Processing, Post-Translational
• Protein Structure, Tertiary
• Proteostasis Deficiencies
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Sequestosome-1 Protein
• Ubiquitination