Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins
Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins
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DOI：
10.1006/nbdi.2001.0405
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发表时间：
2001-08-01
影响因子：
6.1
通讯作者：
Haass, C
中科院分区：
文献类型：
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作者：
Steiner, H;Winkler, E;Haass, C
早老素（PS）蛋白促进选定的I型跨膜蛋白（如阿尔茨海默病（AD）相关的β -淀粉样蛋白前体蛋白（β APP）和Notch）的内蛋白水解。β APP在其跨膜结构域内被一种称为γ -分泌酶的天冬氨酸蛋白酶裂解，其活性可能与PS1和PS2相同。Notch也经历一个依赖ps的膜内蛋白水解。类似的γ -分泌酶样裂解也可能发生在IRE1和ATF6上，这两个未折叠蛋白反应（UPR）的信号分子可能需要ps来激活。在这里，我们分析了ATF6切割是否需要ps依赖性γ -分泌酶活性，以及抑制γ -分泌酶活性是否会影响UPR。在高效y分泌酶抑制剂L-685,458的存在下，观察到ATF6的内源性蛋白水解。ATF6加工也发生在PSI （PS1 D385N）和PS2 （PS2 D366A）的功能失活显性阴性突变体存在时，这些突变体不支持β APP和Notch的内源性蛋白水解。因此，我们的研究结果表明，ATF6不是PS介导的γ -分泌酶样内蛋白水解的底物。这一发现表明，γ -分泌酶抑制剂，目前被开发为降低AD患者大脑中A β负担的治疗药物，不会干扰UPR反应。(C) 2001学术出版社。
Presenilin (PS) proteins facilitate endoproteolysis of selected type I transmembrane proteins such as the Alzheimer's disease (AD) associated beta -Amyloid precursor protein (beta APP) and Notch. beta APP is cleaved within its transmembrane domain by an aspartyl protease activity termed gamma -secretase, which may be identical with PS1 and PS2. Notch also undergoes a PS-dependent intramembraneous proteolysis. A similar gamma -secretase-like cleavage may also occur with IRE1 and ATF6, two signaling molecules of the unfolded protein response (UPR) that may require PSs for their activation. Here, we have analyzed whether ATF6 cleavage requires a PS-dependent gamma -secretase activity and whether inhibition of gamma -secretase activity would affect the UPR. Endoproteolysis of ATF6 was observed in the presence of the highly potent y-secretase inhibitor L-685,458. ATF6 processing also occurred in the presence of functionally inactive dominant negative mutants of PSI (PS1 D385N) and PS2 (PS2 D366A) that do not support endoproteolysis of beta APP and Notch. Our results therefore demonstrate that ATF6 is not a substrate for PS mediated gamma -secretase-like endoproteolysis. This finding indicates that gamma -secretase inhibitors, which are currently developed as therapeutic agents to lower the A beta burden in brains of AD patients, do not interfere with the UPR response. (C) 2001 Academic Press.