Persistent ER stress causes GPI anchor deficit to convert a GPI-anchored prion protein into pro-PrP via the ATF6-miR449c-5p-PIGV axis.
Persistent ER stress causes GPI anchor deficit to convert a GPI-anchored prion protein into pro-PrP via the ATF6-miR449c-5p-PIGV axis.
复制标题
DOI：
10.1016/j.jbc.2023.104982
复制
发表时间：
2023-08
影响因子：
4.8
通讯作者：
Li, Chaoyang
中科院分区：
文献类型：
--
作者：
Li, JingFeng;Li, SaSa;Yu, ShuPei;Yang, Jie;Ke, JingRu;Li, Huan;Chen, Heng;Lu, MingJian;Sy, Man-Sun;Gao, ZhenXing;Li, Chaoyang
内质网(ER)应激和未折叠蛋白反应是细胞的生存策略，以阻止蛋白质平衡的破坏。肿瘤细胞不断受到内质网应激的挑战。PrP通常是一种糖基化磷脂酰肌醇(GPI)锚定蛋白，在人胰腺导管细胞腺癌(PDAC)中以PrP原的形式存在，保留其GPI-肽信号序列。Pro-PrP丰度高提示PDAC患者预后较差。PDAC细胞表达PrP原的原因尚不清楚。在这里，我们报告了持续的内质网应激导致GPI锚定的PrP通过保守的ATF6-miRNA449c-5p-PIGV轴转换为Pro-PrP。小鼠神经元和PDAC细胞株ASPC-1表达GPI锚定的PrP。然而，用内质网应激诱导剂thapsigargin或brefield din A连续培养这些细胞，会导致GPI锚定的PrP转化为Pro-PrP。这种转化是可逆的；去掉诱导剂允许细胞重新表达GPI锚定的PrP。从机制上讲，持续的内质网应激增加了活性ATF6的丰度，从而增加了miRNA449c-5p(miR449c-5p)的水平。MiR449c-5p通过与PIGV的3‘-UTRs结合，抑制了PIGV的水平，PIGV是一种在GPI锚点合成中起关键作用的甘露糖基转移酶。PIGV的减少会导致GPI锚定组装的破坏，导致PrP原积聚，并增强癌细胞的迁移和侵袭。ATF6-miR449c-5p-PIGV轴的重要性在PDAC活检中被概括为高水平的ATF6和miR449c-5p和低水平的PIGV是PDAC患者预后不良的标志。针对这一轴的药物可能会阻止PDAC的进展。
Endoplasmic reticulum (ER) stress and unfolded protein response are cells’ survival strategies to thwart disruption of proteostasis. Tumor cells are continuously being challenged by ER stress. The prion protein, PrP, normally a glycosylphosphatidylinositol (GPI)-anchored protein exists as a pro-PrP retaining its GPI-peptide signal sequence in human pancreatic ductal cell adenocarcinoma (PDAC). Higher abundance of pro-PrP indicates poorer prognosis in PDAC patients. The reason why PDAC cells express pro-PrP is unknown. Here, we report that persistent ER stress causes conversion of GPI-anchored PrP to pro-PrP via a conserved ATF6–miRNA449c-5p–PIGV axis. Mouse neurons and AsPC-1, a PDAC cell line, express GPI-anchored PrP. However, continuous culture of these cells with the ER stress inducers thapsigargin or brefeldin A results in the conversion of a GPI-anchored PrP to pro-PrP. Such a conversion is reversible; removal of the inducers allows the cells to re-express a GPI-anchored PrP. Mechanistically, persistent ER stress increases the abundance of an active ATF6, which increases the level of miRNA449c-5p (miR449c-5p). By binding the mRNA of PIGV at its 3′-UTRs, miR449c-5p suppresses the level of PIGV, a mannosyltransferase pivotal in the synthesis of the GPI anchor. Reduction of PIGV leads to disruption of the GPI anchor assembly, causing pro-PrP accumulation and enhancing cancer cell migration and invasion. The importance of ATF6–miR449c-5p–PIGV axis is recapitulated in PDAC biopsies as the higher levels of ATF6 and miR449c-5p and lower levels of PIGV are markers of poorer outcome for patients with PDAC. Drugs targeting this axis may prevent PDAC progression.
登录
查看更多内容
影响因子：
6.6
作者：
Atkinson, Caroline J.;Kawamata, Futoshi;Wiegmans, Adrian P.
通讯作者：
Wiegmans, Adrian P.
影响因子：
5
作者：
Belmont PJ;Chen WJ;Thuerauf DJ;Glembotski CC
通讯作者：
Glembotski CC
DOI：
10.1073/pnas.85.13.4657
发表时间：
1988-07-01
影响因子：
11.1
作者：
CAUGHEY, B;RACE, RE;CHESEBRO, B
通讯作者：
CHESEBRO, B
影响因子：
--
作者：
Corsaro A;Bajetto A;Thellung S;Begani G;Villa V;Nizzari M;Pattarozzi A;Solari A;Gatti M;Pagano A;Würth R;Daga A;Barbieri F;Florio T
通讯作者：
Florio T
DOI：
10.1038/s41568-020-00312-2
发表时间：
2021-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Chen X;Cubillos-Ruiz JR
通讯作者：
Cubillos-Ruiz JR