Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.
Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.
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DOI：
10.1073/pnas.2300475120
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发表时间：
2023-08
影响因子：
11.1
通讯作者：
Zhou, Chuankai
中科院分区：
文献类型：
--
作者：
Liu, Qingqing;Fong, Benjamin;Yoo, Seungmin;Unruh, Jay R.;Guo, Fengli;Yu, Zulin;Chen, Jingjing;Si, Kausik;Li, Rong;Zhou, Chuankai
老化和环境压力导致蛋白质错误折叠和聚集。目前的范式是，错误折叠的蛋白质凝结成蛋白质聚集体是由于压力引起的普遍存在的蛋白质错误折叠而自主和随机发生的。我们发现保守的线粒体输入受体Tom70和新生线粒体蛋白通过多价疏水相互作用参与胞质蛋白聚集体的局部起始。培养的人类细胞和als相关突变蛋白具有类似的局部聚集机制。虽然冗余的机制也可能有助于细胞质蛋白在线粒体上的局部聚集，但我们的研究提供了无膜凝聚物（蛋白质聚集物）和膜结合细胞器（线粒体）之间机制和功能联系的例子，这是组织细胞内容物的两种主要方式。真核生物将细胞内容物组织成膜结合细胞器和无膜凝聚体，例如蛋白质聚集体。一个尚未解决的问题是，为什么在细胞质中普遍分布的蛋白质会在细胞器表面产生空间定位的蛋白质聚集体，如线粒体。我们报道了线粒体输入受体Tom70参与出芽酵母和人类细胞中蛋白质聚集体的局部凝聚。这是因为错误折叠的细胞质蛋白在体内不能自主聚集；相反，它们被招募到由Tom70的底物（新生线粒体蛋白）在细胞器膜上通过多价疏水相互作用启动的缩合位点。敲除Tom70部分受损，而过表达Tom70增加细胞质蛋白聚集体和线粒体之间的形成和关联。此外，异位靶向Tom70及其底物到液泡表面能够将线粒体的局部聚集重新定向到液泡表面。尽管可能存在其他冗余机制，但这种基于线粒体蛋白质的初始蛋白质聚集可能解释了线粒体上无处不在的分子的局部凝聚。破坏线粒体聚集体的关联会损害它们在有丝分裂期间的不对称保留，并减少错误折叠蛋白质的线粒体进口，这表明细胞器-凝聚物相互作用的蛋白质平衡作用。
Aging and environmental stresses cause protein misfolding and aggregation. The current paradigm is that the condensation of misfolded proteins into protein aggregates happens autonomously and stochastically as a result of ubiquitous protein misfolding induced by stresses. We found that the conserved mitochondrial import receptor Tom70 and nascent mitochondrial proteins are involved in the localized initiation of cytosolic protein aggregates via multivalent hydrophobic interactions. A similar localized aggregation mechanism is shared by the cultured human cells and ALS-linked mutant proteins. Although redundant mechanisms may also contribute to the localized aggregation of cytosolic proteins on mitochondria, our study provides an example of mechanistic and functional connection between membrane-less condensate (protein aggregates) and membrane-bound organelles (mitochondria), two major ways of organizing cellular contents. Eukaryotes organize cellular contents into membrane-bound organelles and membrane-less condensates, for example, protein aggregates. An unsolved question is why the ubiquitously distributed proteins throughout the cytosol give rise to spatially localized protein aggregates on the organellar surface, like mitochondria. We report that the mitochondrial import receptor Tom70 is involved in the localized condensation of protein aggregates in budding yeast and human cells. This is because misfolded cytosolic proteins do not autonomously aggregate in vivo; instead, they are recruited to the condensation sites initiated by Tom70’s substrates (nascent mitochondrial proteins) on the organellar membrane using multivalent hydrophobic interactions. Knocking out Tom70 partially impairs, while overexpressing Tom70 increases the formation and association between cytosolic protein aggregates and mitochondria. In addition, ectopic targeting Tom70 and its substrates to the vacuole surface is able to redirect the localized aggregation from mitochondria to the vacuolar surface. Although other redundant mechanisms may exist, this nascent mitochondrial proteins-based initiation of protein aggregation likely explains the localized condensation of otherwise ubiquitously distributed molecules on the mitochondria. Disrupting the mitochondrial association of aggregates impairs their asymmetric retention during mitosis and reduces the mitochondrial import of misfolded proteins, suggesting a proteostasis role of the organelle-condensate interactions.
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DOI：
10.1083/jcb.201708044
发表时间：
2018-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Backes S;Hess S;Boos F;Woellhaf MW;Gödel S;Jung M;Mühlhaus T;Herrmann JM
通讯作者：
Herrmann JM
低复杂性蛋白段的原子结构揭示了组装网络的扭结β薄片。
DOI：
10.1126/science.aan6398
发表时间：
2018-02-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hughes MP;Sawaya MR;Boyer DR;Goldschmidt L;Rodriguez JA;Cascio D;Chong L;Gonen T;Eisenberg DS
通讯作者：
Eisenberg DS
影响因子：
5.5
作者：
Asadi MR;Rahmanpour D;Moslehian MS;Sabaie H;Hassani M;Ghafouri-Fard S;Taheri M;Rezazadeh M
通讯作者：
Rezazadeh M
影响因子：
64.5
作者：
Albanèse, V;Yam, AYW;Frydman, J
通讯作者：
Frydman, J
DOI：
10.1016/j.bbadis.2018.02.023
发表时间：
2018-09-01
影响因子：
6.2
作者：
He, Chong;Zhou, Chuankai;Kennedy, Brian K.
通讯作者：
Kennedy, Brian K.