Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins
Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins
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DOI：
10.1073/pnas.1216778110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Andreasson, Claes
中科院分区：
文献类型：
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作者：
Gowda, Naveen Kumar Chandappa;Kandasamy, Ganapathi;Andreasson, Claes
蛋白质质量控制系统通过促进选择性降解来保护细胞免受有毒错误折叠蛋白质的积累。质量控制系统的故障与衰老和神经退行性疾病有关。 70 kDa 热休克蛋白 (Hsp70) 分子伴侣的结合促进了多肽的折叠。如果无法实现折叠，Hsp70 会与泛素化酶相互作用，促进错误折叠蛋白的蛋白酶体降解。然而，引导 Hsp70 底物进入降解机制的因素仍然未知。在这里，我们鉴定出 Fes1（一种迄今为止尚不清楚生理功能的 Hsp70 核苷酸交换因子）作为促进错误折叠蛋白的蛋白酶体降解的胞质分类因子。 Fes1 选择性地与 Hsp70 结合的错误折叠蛋白相互作用，并触发它们从分子伴侣中释放。在缺乏 Fes1 的情况下，错误折叠的蛋白质无法进行多泛素化、聚集并诱导强烈的热休克反应。我们的研究结果表明，Hsp70 通过使用不同的核苷酸交换因子引导蛋白质折叠或降解。
Protein quality control systems protect cells against the accumulation of toxic misfolded proteins by promoting their selective degradation. Malfunctions of quality control systems are linked to aging and neurodegenerative disease. Folding of polypeptides is facilitated by the association of 70 kDa Heat shock protein (Hsp70) molecular chaperones. If folding cannot be achieved, Hsp70 interacts with ubiquitylation enzymes that promote the proteasomal degradation of the misfolded protein. However, the factors that direct Hsp70 substrates toward the degradation machinery have remained unknown. Here, we identify Fes1, an Hsp70 nucleotide exchange factor of hitherto unclear physiological function, as a cytosolic triaging factor that promotes proteasomal degradation of misfolded proteins. Fes1 selectively interacts with misfolded proteins bound by Hsp70 and triggers their release from the chaperone. In the absence of Fes1, misfolded proteins fail to undergo polyubiquitylation, aggregate, and induce a strong heat shock response. Our findings reveal that Hsp70 direct proteins toward either folding or degradation by using distinct nucleotide exchange factors.