Dynamic intracellular exchange of nanomaterials' protein corona perturbs proteostasis and remodels cell metabolism.
Dynamic intracellular exchange of nanomaterials' protein corona perturbs proteostasis and remodels cell metabolism.
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DOI：
10.1073/pnas.2200363119
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发表时间：
2022-06-07
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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这项研究分析了纳米颗粒表面的动态蛋白质冠，因为它们从血液穿过细胞溶酶体，并从溶酶体逃逸到靶细胞的细胞质。我们通过蛋白质组学分析发现了大量的伴侣蛋白和糖酵解冠状蛋白（即，热休克同源蛋白70、热休克蛋白90和丙酮酸激酶M2 [PKM 2]）。冠状蛋白的改变（例如，PKM 2和伴侣蛋白结合）诱导蛋白质稳态崩溃，随后导致细胞中伴侣蛋白介导的自噬（CMA）活性升高。由于PKM 2是细胞代谢的关键分子，我们还发现PKM 2缺失是CMA诱导的细胞代谢从糖酵解到脂质代谢中断的原因。纳米材料-蛋白质“冠”是一个动态实体，提供了一个合成-天然界面，介导生物系统中纳米材料的细胞摄取和亚细胞分布。由于纳米材料是未来纳米医学安全设计和纳米安全实践的核心，理解和描绘无处不在的纳米材料蛋白质冠的生物和毒理学特征是纳米生物科学和工程持续发展的前体。然而，尽管进行了十多年的广泛研究，但在纳米材料的细胞内化后，其细胞内释放或交换血液蛋白质冠的动力学仍然不清楚，纳米颗粒-蛋白质冠穿越细胞区室的生物足迹甚至更不清楚。为了解决这一关键瓶颈，目前的工作筛选了癌细胞内蛋白质冠沿着从血液经溶酶体到细胞质的内吞途径的进化。细胞间蛋白质，包括丙酮酸激酶M2（PKM 2）和分子伴侣，取代了一些最初吸附的血液蛋白从纳米颗粒表面，扰乱蛋白质稳态，随后引发分子伴侣介导的自噬（CMA）破坏关键的细胞代谢途径，包括糖酵解和脂质代谢。由于蛋白质稳态是细胞功能可持续性的关键，其崩溃和由此产生的CMA预示着随后的细胞死亡和衰老。我们的研究结果揭示了纳米颗粒转运细胞外蛋白对细胞代谢的影响。
This study analyzed the dynamic protein corona on the surface of nanoparticles as they traversed from blood to cell lysosomes and escaped from lysosomes to cytoplasm in the target cells. We found with proteomic analysis an abundance of chaperone and glycolysis coronal proteins (i.e., heat shock cognate protein 70, heat shock protein 90, and pyruvate kinase M2 [PKM2]) after escape of the nanoparticles from lysosomes to the cytosol. Alterations of the coronal proteins (e.g., PKM2 and chaperone binding) induced proteostasis collapse, which subsequently led to elevated chaperone-mediated autophagy (CMA) activity in cells. As PKM2 is a key molecule in cell metabolism, we also revealed that PKM2 depletion was causative to CMA-induced cell metabolism disruption from glycolysis to lipid metabolism. The nanomaterial–protein “corona” is a dynamic entity providing a synthetic–natural interface mediating cellular uptake and subcellular distribution of nanomaterials in biological systems. As nanomaterials are central to the safe-by-design of future nanomedicines and the practice of nanosafety, understanding and delineating the biological and toxicological signatures of the ubiquitous nanomaterial–protein corona are precursors to the continued development of nano–bio science and engineering. However, despite well over a decade of extensive research, the dynamics of intracellular release or exchange of the blood protein corona from nanomaterials following their cellular internalization remains unclear, and the biological footprints of the nanoparticle–protein corona traversing cellular compartments are even less well understood. To address this crucial bottleneck, the current work screened evolution of the intracellular protein corona along the endocytotic pathway from blood via lysosomes to cytoplasm in cancer cells. Intercellular proteins, including pyruvate kinase M2 (PKM2), and chaperones, displaced some of the initially adsorbed blood proteins from the nanoparticle surface, which perturbed proteostasis and subsequently incited chaperone-mediated autophagy (CMA) to disrupt the key cellular metabolism pathway, including glycolysis and lipid metabolism. Since proteostasis is key to the sustainability of cell function, its collapse and the resulting CMA overdrive spell subsequent cell death and aging. Our findings shed light on the consequences of the transport of extracellular proteins by nanoparticles on cell metabolism.
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伴侣介导的自噬的时代的到来。
DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Kaushik S;Cuervo AM
通讯作者：
Cuervo AM
影响因子：
2.1
作者：
Dekiwadia, Chaitali D.;Lawrie, Ann C.;Fecondo, John V.
通讯作者：
Fecondo, John V.
影响因子：
38.3
作者：
Jiang, Xingya;Du, Bujie;Zheng, Jie
通讯作者：
Zheng, Jie
影响因子：
17.1
作者：
Bertoli, Filippo;Garry, David;Dawson, Kenneth A.
通讯作者：
Dawson, Kenneth A.
影响因子：
17.1
作者：
Billing, Anja M.;Knudsen, Kristina B.;Kjeldsen, Frank
通讯作者：
Kjeldsen, Frank