Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress
Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress
复制标题
DOI：
10.1074/jbc.m109.093799
复制
发表时间：
2010-05-28
影响因子：
4.8
通讯作者：
Hwang, Onyou
中科院分区：
文献类型：
--
作者：
Kim, Eun-Mee;Shin, Eun-Jung;Hwang, Onyou
虽然内质网（ER）应激诱导的细胞凋亡与神经退行性疾病的发病机制有关，但涉及的细胞成分尚未得到很好的描述。目前的研究表明，基质金属蛋白酶（MMP）-3在内质网应激诱导的细胞凋亡中发挥作用。由布雷菲德菌素A（BFA）或衣霉素（TM）诱导的ER应激增加MMP-3的基因表达，在各种MMP亚型中选择性地增加MMP-3的基因表达，以及脑源性CATH中MMP-3的活性形式（actMMP-3）。a细胞。酶活性的药理学抑制、小干扰RNA介导的基因敲除和MMP-3的基因敲除都提供了针对ER应激的保护。MMP-3作用于caspase-12的下游，因为caspase-12的药理学抑制和基因敲除都会减弱actMMP-3的增加，但MMP-3的抑制和敲除不会改变caspase-12。此外，与蛋白质水平的增加无关，MMP-3酶的催化活性可以通过降低其内源性抑制蛋白TIMP-1而增加。胱天蛋白酶-12通过降解已经与actMMP-3结合的TIMP-1导致MMP-3酶活性的释放。TIMP-1响应于ER应激而降低，并且TIMP-1过表达导致细胞保护和MMP-3活性降低。两者合计，actMMP-3蛋白水平和催化活性增加后，半胱天冬酶-12激活在ER应激，这反过来又发挥了作用，在神经元细胞的下游凋亡信号。因此，MMP-3和TIMP-1可以作为治疗神经退行性疾病的细胞靶点。
Although endoplasmic reticulum (ER) stress-induced apoptosis has been associated with pathogenesis of neurodegenerative diseases, the cellular components involved have not been well delineated. The present study shows that matrix metalloproteinase (MMP)-3 plays a role in the ER stress-induced apoptosis. ER stress induced by brefeldin A (BFA) or tunicamycin (TM) increases gene expression of MMP-3, selectively among various MMP subtypes, and the active form of MMP-3 (actMMP-3) in the brain-derived CATH. a cells. Pharmacological inhibition of enzyme activity, small interference RNA-mediated gene knockdown, and gene knock-out of MMP-3 all provide protection against ER stress. MMP-3 acts downstream of caspase-12, because both pharmacological inhibition and gene knockdown of caspase-12 attenuate the actMMP-3 increase, but inhibition and knock-out of MMP-3 do not alter caspase-12. Furthermore, independently of the increase in the protein level, the catalytic activity of MMP-3 enzyme can be increased via lowering of its endogenous inhibitor protein TIMP-1. Caspase-12 causes liberation of MMP-3 enzyme activity by degrading TIMP-1 that is already bound to actMMP-3. TIMP-1 is decreased in response to ER stress, and TIMP-1 overexpression leads to cell protection and a decrease in MMP-3 activity. Taken together, actMMP-3 protein level and catalytic activity are increased following caspase-12 activation during ER stress, and this in turn plays a role in the downstream apoptotic signaling in neuronal cells. MMP-3 and TIMP-1 may therefore serve as cellular targets for therapy against neurodegenerative diseases.