ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling.
ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling.
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DOI：
10.1016/j.mcn.2016.08.004
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Layfield R
中科院分区：
文献类型：
--
作者：
Goode A;Rea S;Sultana M;Shaw B;Searle MS;Layfield R
转录因子Nrf 2及其阻遏蛋白Keap 1在调节抗氧化应激反应中起关键作用，Keap 1-Nrf 2信号传导和氧化应激均与神经退行性疾病的ALS-FTLD谱的发病机制有关。Keap 1结合伴侣和自噬受体SQSTM 1/p62最近也与ALS-FTLD遗传相关，在患者中发现了一些错义突变，这些错义突变位于其Keap 1相互作用区域（KIR，残基347-352）内或附近。在这里，我们报告了影响KIR区域的SQSTM 1/p62的四种不同疾病相关突变对蛋白质功能的影响。只有精确定位于KIR的突变（P348 L和G351 A）与免疫共沉淀中Keap 1结合的丧失相关，与野生型SQSTM 1/p62相当。基于蛋白质结构模型，这些对Keap 1识别的选择性效应是完全合理的。与受损的Keap 1结合一致，P348 L和G351 A KIR突变体在抗氧化反应元件（ARE）-荧光素酶报告基因测定中显示与野生型SQSTM 1/p62相比激活Nrf 2信号传导的能力降低。结果表明，SQSTM 1/p62的KIR内的SQSTM 1突变通过涉及氧化反应基因的异常表达或调节的机制促成了某些ALS-FTLD病例的病因学。ALS-FTLD相关的SQSTM 1/p62 KIR突变破坏Keap 1结合。SQSTM 1/p62的KIR突变体在报告基因测定中不能激活Nrf 2信号传导。一些SQSTM 1突变可能通过异常的抗氧化应激反应导致ALS-FTLD。
The transcription factor Nrf2 and its repressor protein Keap1 play key roles in the regulation of antioxidant stress responses and both Keap1-Nrf2 signalling and oxidative stress have been implicated in the pathogenesis of the ALS-FTLD spectrum of neurodegenerative disorders. The Keap1-binding partner and autophagy receptor SQSTM1/p62 has also recently been linked genetically to ALS-FTLD, with some missense mutations identified in patients mapping within or close to its Keap1-interacting region (KIR, residues 347–352). Here we report the effects on protein function of four different disease associated mutations of SQSTM1/p62 which affect the KIR region. Only mutations mapping precisely to the KIR (P348L and G351A) were associated with a loss of Keap1 binding in co-immunoprecipitations comparable to wild-type SQSTM1/p62. These selective effects on Keap1 recognition were entirely rational based on protein structural models. Consistent with impaired Keap1 binding, the P348L and G351A KIR mutants showed reduced ability to activate Nrf2 signalling compared to wild-type SQSTM1/p62 in antioxidant response element (ARE)-luciferase reporter assays. The results suggest that SQSTM1 mutations within the KIR of SQSTM1/p62 contribute to aetiology of some cases of ALS-FTLD through a mechanism involving aberrant expression or regulation of oxidative response genes. ALS-FTLD associated KIR mutations of SQSTM1/p62 disrupt Keap1 binding. KIR mutants of SQSTM1/p62 are unable to activate Nrf2 signalling in reporter assays. Some SQSTM1 mutations may contribute to ALS-FTLD through an aberrant antioxidant stress response.
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DOI：
10.1016/j.bbadis.2014.03.006
发表时间：
2014-07
影响因子：
6.2
作者：
Goode, Alice;Long, Jed E.;Shaw, Barry;Ralston, Stuart H.;Visconti, Micaela Rios;Gianfrancesco, Fernando;Esposito, Teresa;Gennari, Luigi;Merlotti, Daniela;Rendina, Domenico;Rea, Sarah L.;Sultana, Melanie;Searle, Mark S.;Layfield, Robert
通讯作者：
Layfield, Robert
影响因子：
3.5
作者：
Majcher, Veronika;Goode, Alice;Layfield, Robert
通讯作者：
Layfield, Robert
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1074/jbc.m109.096545
发表时间：
2010-05-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Copple IM;Lister A;Obeng AD;Kitteringham NR;Jenkins RE;Layfield R;Foster BJ;Goldring CE;Park BK
通讯作者：
Park BK
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki