title: ENC1 Modulates the Aggregation and Neurotoxicity of Mutant Huntingtin Through p62 Under ER Stress.
abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder, which is caused by the expression and aggregation of polyQ-expanded mutant huntingtin protein (mtHTT). While toxic mtHTT aggregates are primarily eliminated through autophagy, autophagy dysfunction is often observed in HD pathogenesis. Here, we show that ectodermal-neural cortex 1 (ENC1), a novel binding partner of sequestosome 1 (p62), negatively regulates autophagy under endoplasmic reticulum (ER) stress. We found that ER stress significantly increases the expression of ENC1 via inositol-requiring enzyme 1 (IRE1)-TNF receptor-associated factor 2 (TRAF2)-c-Jun N-terminal kinase (JNK) pathway. Ectopic expression of ENC1 alone induces the accumulation of detergent-resistant mtHTT aggregates and downregulation of ENC1 alleviates ER stress-induced mtHTT aggregation. Simultaneously, ER stress-induced impairment of autophagy flux is ameliorated by downregulation of ENC1. From immunoprecipitation and immunocytochemical assays, we found that ENC1 binds to p62 through its BTB and C-terminal Kelch (BACK) domain and this interaction is enhanced under ER stress. In particular, ENC1 preferentially interacts with the phosphorylated p62 at Ser403 during ER stress. Interestingly, ENC1 colocalizes with mtHTT aggregates and its C-terminal Kelch domain is required for interfering with the access of p62 to ubiquitinated mtHTT aggregates, thus inhibiting cargo recognition of p62. Accordingly, knockdown of ENC1 expression enhances colocalization of p62 with mtHTT aggregates. Consequently, ENC1 knockdown relieves death of neuronal cells expressing mtHTT under ER stress. These results suggest that ENC1 interacts with the phosphorylated p62 to impair autophagic degradation of mtHTT aggregates and affects cargo recognition failure under ER stress, leading to the accumulation and neurotoxicity of mtHTT aggregates.
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Huikyong
authors.initials: H
authors.lastname: Lee
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hye-Hyun
authors.initials: HH
authors.lastname: Ahn
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: WonJae
authors.initials: W
authors.lastname: Lee
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.|Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, 21231, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Choi
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shim
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute, Suwon-Si, Kyonggi-Do, 440-746, South Korea.
authors.forename: Jaekyoon
authors.initials: J
authors.lastname: Shin
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, 151-742, South Korea. ykjung@snu.ac.kr.
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D050505:Mutant Proteins / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism
chemical_list: D000071058:Huntingtin Protein; D008840:Microfilament Proteins; D050505:Mutant Proteins; D009479:Neuropeptides; D009498:Neurotoxins; D009687:Nuclear Proteins; D066329:Protein Aggregates; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D047992:TNF Receptor-Associated Factor 2; C112302:ectodermal-neural cortex 1 protein; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; D046988:Proteasome Endopeptidase Complex
keywords: Aggregation; Autophagy; ENC1; ER stress; Huntington’s disease; p62/SQSTM1