Global Proteotoxicity Caused by Human β(2) Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans.
Global Proteotoxicity Caused by Human β(2) Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans.
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DOI：
10.3390/ijms221910752
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发表时间：
2021-10-04
影响因子：
5.6
通讯作者：
van Oosten-Hawle P
中科院分区：
文献类型：
--
作者：
Good SC;Dewison KM;Radford SE;van Oosten-Hawle P
β2微球蛋白(β2M)聚集成淀粉样纤维与系统性淀粉样变性有关，这是由于血液透析患者中含有野生型蛋白及其截短变体ΔN6β2M的淀粉样纤维沉积所致。第二种形式的家族性系统性淀粉样变性由β2M变异D76N引起，导致内脏淀粉样蛋白沉积，而没有肾功能障碍。尽管β2微球蛋白的折叠和错误折叠机制在体外和体内都得到了广泛的研究，但我们对细胞和生物环境中潜在毒性的分子机制缺乏类似的了解。在这里，我们建立了在线虫体壁肌肉中表达野生型(WT)人β2M或两个高度淀粉样变异体--D76Nβ2M和ΔN6β2M的转基因线虫。表达D76Nβ2M和ΔN6β2M变体的线虫表现出年龄依赖性和细胞非自主蛋白毒性增加，与运动性降低、发育延迟和寿命缩短有关。这两个β2M变异体都会引起广泛的内源性蛋白质聚集，从而导致老年动物的毒性增加。我们发现β2M的表达降低了线虫应对热和内质网(ER)压力的能力，这与年轻成年动物缺乏上调BIP/HSP-4转录以应对ER压力有关。有趣的是，尽管存在自然信号序列，但所有β2M变体的蛋白质分泌都减少了，这表明有机β2M毒性与ER分泌代谢紊乱之间可能存在联系。
Aggregation of β2 microglobulin (β2m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 β2m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β2m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β2 microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human β2m, or the two highly amyloidogenic naturally occurring variants, D76N β2m and ΔN6 β2m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β2m and ΔN6 β2m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β2m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β2m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all β2m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β2m toxicity and a disrupted ER secretory metabolism.
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影响因子：
15
作者：
Hoop, Cody L.;Zhu, Jie;Baum, Jean
通讯作者：
Baum, Jean
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
--
作者：
Han SK;Lee D;Lee H;Kim D;Son HG;Yang JS;Lee SV;Kim S
通讯作者：
Kim S
DOI：
10.1074/jbc.m113.498857
发表时间：
2013-10-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mangione PP;Esposito G;Relini A;Raimondi S;Porcari R;Giorgetti S;Corazza A;Fogolari F;Penco A;Goto Y;Lee YH;Yagi H;Cecconi C;Naqvi MM;Gillmore JD;Hawkins PN;Chiti F;Rolandi R;Taylor GW;Pepys MB;Stoppini M;Bellotti V
通讯作者：
Bellotti V
DOI：
10.1074/jbc.m114.586222
发表时间：
2014-12-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jakhria T;Hellewell AL;Porter MY;Jackson MP;Tipping KW;Xue WF;Radford SE;Hewitt EW
通讯作者：
Hewitt EW