Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins
Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins
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DOI：
10.1042/bj20061451
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Fraser, Paul E.
中科院分区：
文献类型：
--
作者：
Dorval, Veronique;Mazzella, Matthew J.;Fraser, Paul E.
β-和γ-分泌酶对APP（淀粉样前体蛋白）的连续加工以及A β（淀粉样）肽的产生是AD（阿尔茨海默病）的主要病理因素。调节这些蛋白质的加工或周转是开发AD疗法的潜在靶点。SUMO化是SUMO（小泛素样修饰物）与靶蛋白共价结合的过程，导致许多功能性结果。这些包括调节蛋白质-蛋白质相互作用、细胞内运输和蛋白质稳定性，这些都有可能影响淀粉样蛋白生成途径的几个方面。本研究探讨了过表达和敲除主要的SUMO亚型（SUMO 1，2和3）对APP加工和A肽产生的影响。SUMO 3过表达显著增加A 40和A 42的分泌，这伴随着全长APP及其C-末端片段的增加。SUMO 3的这些作用与其共价连接或链形成无关，因为缺乏负责SUMO链形成或SUMO缀合的基序的突变体导致A β的类似变化。SUMO 3过表达也上调了跨膜蛋白酶BACE（β-淀粉样蛋白裂解酶）的表达，但未能影响其他几种无关蛋白的水平。通过RNA干扰抑制SUMO 1或组合SUMO 2 + 3不影响APP水平或A β产生。这些发现证实了SUMO 3过表达对APP加工和A β肽产生的特异性作用，但也表明内源性SUMO化不是必需的，并且可能在调节淀粉样蛋白加工途径中起间接作用。
The sequential processing of the APP (amyloid precursor protein) by the beta- and gamma-secretase and generation of the A beta (amyloid) peptide is a primary pathological factor in AD (Alzheimer's disease). Regulation of the processing or turnover of these proteins represents potential targets for the development of AD therapies. Sumoylation is a process by which SUMOs (small ubiquitin-like modifiers) are covalently conjugated to target proteins, resulting in a number of functional consequences. These include regulation of protein-protein interactions, intracellular trafficking and protein stability, which all have the potential to impact on several aspects of the amyloidogenic pathway. The present study examines the effects of overexpression and knockdown of the major SUMO isoforms (SUMO 1, 2 and 3) on APP processing and the production of A peptides. SUMO3 overexpression significantly increased A 40 and A 42 secretion, which was accompanied by an increase in full-length APP and its C-terminal fragments. These effects of SUMO3 were independent of its covalent attachment or chain formation, as mutants lacking the motifs responsible for SUMO chain formation or SUMO conjugation led to similar changes in A beta. SUMO3 overexpression also up-regulated the expression of the transmembrane protease BACE (beta-amyloid-cleaving enzyme), but failed to affect levels of several other unrelated proteins. Suppression of SUMO1 or combined SUMO2 + 3 by RNA interference did not affect APP levels or A beta production. These findings confirm a specific effect of SUMO3 overexpression on APP processing and the production of A beta peptides but also suggest that endogenous sumoylation is not essential and likely plays an indirect role in modulating the amyloid processing pathway.