CD317 maintains proteostasis and cell survival in response to proteasome inhibitors by targeting calnexin for RACK1-mediated autophagic degradation.
CD317 maintains proteostasis and cell survival in response to proteasome inhibitors by targeting calnexin for RACK1-mediated autophagic degradation.
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DOI：
10.1038/s41419-023-05858-1
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发表时间：
2023-05-20
影响因子：
9
通讯作者：
Yu, Guang
中科院分区：
文献类型：
--
作者：
Cheng, Jian;Zhang, Guizhong;Deng, Tian;Liu, Zhao;Zhang, Mengqi;Zhang, Pengchao;Adeshakin, Funmilayo O.;Niu, Xiangyun;Yan, Dehong;Wan, Xiaochun;Yu, Guang
不平衡的蛋白质稳态(蛋白质稳态)网络经常与肿瘤的发生有关，使癌细胞更容易受到针对蛋白质稳态调节剂的治疗的影响。蛋白酶体抑制是第一个获得许可的蛋白稳定靶向治疗策略，已被证明对血液系统恶性肿瘤患者有效。然而，耐药性的产生几乎是不可避免的，迫切需要更好地了解维持肿瘤细胞蛋白稳定的机制。在此，我们报道了CD317，一种具有独特拓扑结构的肿瘤靶向抗原，在血液系统恶性肿瘤中上调，并在蛋白酶体抑制剂(PI)的响应下保持蛋白稳定和细胞活力。下调CD317可降低内质网(ER)内的钙离子水平，促进Pis诱导的蛋白稳定失效和细胞死亡。在机制上，CD317与内质网伴侣蛋白Calnexin(CNX)相互作用，通过钙泵SERCA限制钙再充盈，从而使CNX经历RACK1介导的自噬降解。因此，CD317降低了CNX蛋白的水平，协调了钙离子的摄取，从而有利于内质网管腔内蛋白质的折叠和质量控制。我们的发现揭示了CD317在蛋白调控中先前未知的作用，并暗示CD317可能是临床上解决PI耐药性的一个有前途的靶点。
Unbalanced protein homeostasis (proteostasis) networks are frequently linked to tumorigenesis, making cancer cells more susceptible to treatments that target proteostasis regulators. Proteasome inhibition is the first licensed proteostasis-targeting therapeutic strategy, and has been proven effective in hematological malignancy patients. However, drug resistance almost inevitably develops, pressing for a better understanding of the mechanisms that preserve proteostasis in tumor cells. Here we report that CD317, a tumor-targeting antigen with a unique topology, was upregulated in hematological malignancies and preserved proteostasis and cell viability in response to proteasome inhibitors (PIs). Knocking down CD317 lowered Ca2+ levels in the endoplasmic reticulum (ER), promoting PIs-induced proteostasis failure and cell death. Mechanistically, CD317 interacted with calnexin (CNX), an ER chaperone protein that limits calcium refilling via the Ca2+ pump SERCA, thereby subjecting CNX to RACK1-mediated autophagic degradation. As a result, CD317 decreased the level of CNX protein, coordinating Ca2+ uptake and thus favoring protein folding and quality control in the ER lumen. Our findings reveal a previously unrecognized role of CD317 in proteostasis control and imply that CD317 could be a promising target for resolving PIs resistance in the clinic.
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DOI：
10.1083/jcb.201709072
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Klaips CL;Jayaraj GG;Hartl FU
通讯作者：
Hartl FU
影响因子：
7.7
作者：
Preissler S;Rato C;Yan Y;Perera LA;Czako A;Ron D
通讯作者：
Ron D
影响因子：
13.3
作者：
Milan E;Perini T;Resnati M;Orfanelli U;Oliva L;Raimondi A;Cascio P;Bachi A;Marcatti M;Ciceri F;Cenci S
通讯作者：
Cenci S
BST2 通过选择性自噬靶向和降解病毒核衣壳蛋白来抑制猪流行性腹泻病毒复制
影响因子：
13.3
作者：
Kong, Ning;Shan, Tongling;Tong, Guangzhi
通讯作者：
Tong, Guangzhi
影响因子：
5.4
作者：
Habermann, Anja;Krijnse-Locker, Jacomine;Kraeusslich, Hans-Georg
通讯作者：
Kraeusslich, Hans-Georg