Derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 is has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.

蛋白质聚集是病变细胞与衰老细胞的常见特征。膜蛋白占细胞蛋白质组的四分之一，但目前学界对膜蛋白聚集的调控机制，以及此类聚集对细胞健康的具体影响尚未被充分阐明。我们在酵母模型中研究发现，DERLIN蛋白Dfm1具有类分子伴侣活性，可调控错误折叠膜蛋白的聚集过程。我们证实，Dfm1的该功能无需招募ATP酶Cdc48，且有别于其此前被报道的、将错误折叠膜蛋白转位至细胞质基质以进行降解的经典功能。此外，我们还评估了缺失Dfm1时错误折叠膜蛋白对细胞的影响，结果表明，在Dfm1缺失的情况下，错误折叠膜蛋白会对细胞产生毒性，并破坏蛋白酶体稳态与泛素稳态。