The PKCδ-Abl complex communicates ER stress to the mitochondria -: an essential step in subsequent apoptosis
The PKCδ-Abl complex communicates ER stress to the mitochondria -: an essential step in subsequent apoptosis
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DOI：
10.1242/jcs.024653
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发表时间：
2008-03-15
影响因子：
4
通讯作者：
Mochly-Rosen, Daria
中科院分区：
文献类型：
--
作者：
Qi, Xin;Mochly-Rosen, Daria
内质网中蛋白质折叠受损的条件触发未折叠蛋白反应（UPR），其要么恢复适当的蛋白质折叠，要么通过细胞凋亡导致细胞死亡。在本研究中，我们发现，在体内和体外对内质网应激的反应中，PKC delta易位到内质网，并与酪氨酸激酶Abl结合。酪氨酸磷酸化和PKC δ激酶活性是PKC δ与内质网中Abl结合所必需的。此外，我们发现PKC δ特异性肽抑制剂delta V1-1或PKC δ沉默抑制PKC δ可减少内质网应激诱导的JNK激活并抑制内质网应激介导的细胞凋亡。此外，PKC δ激酶活性抑制剂rottlerin阻断PKC δ - abl复合物从内质网到线粒体的易位，并赋予细胞凋亡保护作用。因此，PKC δ通过结合内质网定位的Abl将内质网应激传递给线粒体。PKC δ - abl复合体随后易位到线粒体，将内质网应激传递给该细胞器，从而引发细胞凋亡。
Conditions that compromise protein folding in the endoplasmic reticulum trigger the unfolded protein response (UPR), which either restores proper protein folding or results in cellular demise through apoptosis. In this study, we found that, in response to ER stress in vivo and in vitro, PKC delta translocates to the ER where it binds to the tyrosine kinase Abl. Tyrosine phosphorylation and kinase activity of PKC delta are required for PKC delta binding to Abl in the ER. Moreover, we found that inhibition of PKC delta by the PKC delta-specific peptide inhibitor delta V1-1 or by silencing of PKC delta reduces ER-stress-induced JNK activation and inhibits ER-stress-mediated apoptosis. Furthermore, the inhibitor of PKC delta kinase activity rottlerin blocks the translocation of the PKC delta-Abl complex from the ER to the mitochondria and confers protection against apoptosis. Thus, PKC delta communicates ER stress to the mitochondria by binding to ER-localized Abl. The PKC delta-Abl complex then translocates to the mitochondria, communicating ER stress to this organelle, thereby, triggering apoptosis.