Interaction with ERp57 is required for progranulin protection against Type 2 Gaucher disease.
Interaction with ERp57 is required for progranulin protection against Type 2 Gaucher disease.
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DOI：
10.5582/bst.2023.01022
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发表时间：
2023-05-15
影响因子：
5.5
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Liu Y;Zhao X;Jian J;Hasan S;Liu C
高谢病(GD)是最常见的溶酶体储存性疾病之一，其原因是GCAE基因突变导致葡萄糖脑苷酶(GCase)缺陷，导致其底物β-葡萄糖神经酰胺(β-GlcCer)积聚。我们报道了分泌型生长因子样分子前颗粒蛋白(PGRN)和细胞内溶酶体蛋白是GCase的关键辅助因子。PGRN与GCase结合，通过其C-末端颗粒蛋白(Grn)E结构域，将热休克蛋白70(Hsp70)招募到GCase，称为ND7。此外，PGRN和ND7对GD均有治疗作用。在此，我们发现在Hsp70缺陷的细胞中，PGRN及其衍生的ND7仍然对GD具有显著的保护作用。为了阐明PGRN对GD的非依赖性调控的分子机制，我们对Hsp70缺陷细胞进行了His标记的PGRN和His标记的ND7的生化共纯化和质谱分析，从而鉴定了ERp57，也被称为蛋白质二硫键异构酶A3(PDIA3)，是一种同时与PGRN和ND7结合的蛋白质。在携带GBA1L444P突变的2型神经病理性GD患者成纤维细胞L444P中，ERp57的缺失在很大程度上取消了PGRN和ND7的治疗作用，表现为对溶酶体储存、GCase活性和β-GlcCer积聚的影响。此外，重组ERp57有效地恢复了PGRN和ND7对ERp57基因敲除的L444P成纤维细胞的治疗作用。综上所述，本研究报告ERp57是先前未被识别的PGRN结合伙伴，参与PGRN对GD的调控。
Gaucher disease (GD), one of the most common lysosomal storage diseases, is caused by GBA1 mutations resulting in defective glucocerebrosidase (GCase) and consequent accumulation of its substrates β-glucosylceramide (β-GlcCer). We reported progranulin (PGRN), a secretary growth factor-like molecule and an intracellular lysosomal protein was a crucial co-factor of GCase. PGRN binds to GCase and recruits Heat Shock Protein 70 (Hsp70) to GCase through its C-terminal Granulin (Grn) E domain, termed as ND7. In addition, both PGRN and ND7 are therapeutic against GD. Herein we found that both PGRN and its derived ND7 still displayed significant protective effects against GD in Hsp70 deficient cells. To delineate the molecular mechanisms underlying PGRN’s Hsp70-independent regulation of GD, we performed a biochemical co-purification and mass spectrometry with His-tagged PGRN and His-tagged ND7 in Hsp70 deficient cells, which led to the identification of ERp57, also referred to as protein disulfide isomerase A3 (PDIA3), as a protein that binds to both PGRN and ND7. Within type 2 neuropathic GD patient fibroblasts L444P, bearing GBA1 L444P mutation, deletion of ERp57 largely abolished the therapeutic effects of PGRN and ND7, as manifested by loss of effects on lysosomal storage, GCase activity, and β-GlcCer accumulation. Additionally, recombinant ERp57 effectively restored the therapeutic effects of PGRN and ND7 in ERp57 knockout L444P fibroblasts. Collectively, this study reports ERp57 as a previously unrecognized binding partner of PGRN that contributes to PGRN regulation of GD.
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影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
3.4
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1038/nrn.2017.36
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
Ventura, Andrea