SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation
SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation
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SIP/CacyBP 通过调节 BRUCE/Apollon 的水平来促进自噬，从而刺激 LC3-I 降解
DOI：
10.1073/pnas.1901039116
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发表时间：
2019-07-02
影响因子：
11.1
通讯作者：
Qiu, Xiao-Bo
中科院分区：
文献类型：
--
作者：
Jiang, Tian-Xia;Zou, Jiang-Bo;Qiu, Xiao-Bo
布鲁斯/Apollon是一种细胞凋亡蛋白的膜相关抑制剂，对生存力至关重要，并具有泛素缀合活性。在细胞凋亡开始时，泛素连接酶Nrdp 1/RNF 41促进布鲁斯的蛋白酶体降解。在这里，我们证明了布鲁斯与蛋白酶体激活剂PA 28 γ一起导致LC 3-I的蛋白酶体降解，从而抑制自噬。吞噬细胞膜上的LC 3-I与磷脂酰乙醇胺缀合形成LC 3-II，其是形成自噬体和选择性募集底物所需的。SIP/CacyBP是一种泛素化相关蛋白，在神经元和各种肿瘤中高度表达。在正常条件下，SIP抑制布鲁斯的泛素化和降解，可能是通过阻断Nrdp 1与布鲁斯的结合。在拓扑异构酶抑制剂引起的DNA损伤中，Nrdp 1引起SIP的单泛素化，从而促进细胞凋亡。然而，在饥饿时，SIP与Rab 8一起增强布鲁斯易位到再循环内体中，形成自噬体，并通过视神经氨酸介导的自噬降解布鲁斯。因此，培养细胞中SIP的缺失减少了受损线粒体和胞质蛋白质聚集体的自噬降解。因此，通过刺激LC 3-I的蛋白酶体降解，布鲁斯也抑制自噬。相反，SIP通过阻断LC 3-I的BRUCE依赖性降解以及通过增强布鲁斯的自噬体形成和自噬破坏来促进自噬。布鲁斯和SIP的这些作用代表了在不同条件下连接自噬和凋亡调节的机制。
BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28 gamma causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanol-amine to form LC3-II, which is required for the formation of auto-phagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions.