期刊
AUTOPHAGY
卷 12, 期 7, 页码 1094-1104出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2016.1170257
关键词
ALS; Atg8; LC3; autophagy; FTLD; LIR; SQSTM1; p62
类别
资金
- MND Association [821-791]
- University of Nottingham
- BBSRC [BB/I011420/1]
- Wellcome Trust Equipment Grant [094233/Z/10/Z]
- BBSRC [BB/F019297/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F019297/1, BB/I011420/1] Funding Source: researchfish
- Motor Neurone Disease Association [Layfield/Apr13/821-791] Funding Source: researchfish
Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a approximate to 3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据