Institute for Biomedicine, Sahlgrenska Academy, Center for Aging and Health-AgeCap, University of Gothenburg, Sweden.
Center for Bionics and Pain Research, Sahlgrenska University Hospital, Mölndal, Sweden.
FEBS J. 2023 Oct;290(19):4744-4761. doi: 10.1111/febs.16886. Epub 2023 Jun 20.
The small heat shock protein Hsp42 and the t-SNARE protein Sed5 have central roles in the sequestration of misfolded proteins into insoluble protein deposits in the yeast Saccharomyces cerevisiae. However, whether these proteins/processes interact in protein quality control (PQC) is not known. Here, we show that Sed5 and anterograde trafficking modulate phosphorylation of Hsp42 partially via the MAPK kinase Hog1. Such phosphorylation, specifically at residue S215, abrogated the co-localization of Hsp42 with the Hsp104 disaggregase, aggregate clearance, chaperone activity, and sequestration of aggregates to IPOD and mitochondria. Furthermore, we found that Hsp42 is hyperphosphorylated in old cells leading to a drastic failure in disaggregation. Old cells also displayed a retarded anterograde trafficking, which, together with slow aggregate clearance and hyperphosphorylation of Hsp42, could be counteracted by Sed5 overproduction. We hypothesize that the breakdown of proper PQC during yeast aging may, in part, be due to a retarded anterograde trafficking leading to hyperphosphorylation of Hsp42.
小分子热休克蛋白 Hsp42 和 t-SNARE 蛋白 Sed5 在酵母酿酒酵母中将错误折叠的蛋白质隔离到不溶性蛋白质沉积物中起着核心作用。然而，这些蛋白质/过程是否在蛋白质质量控制 (PQC) 中相互作用尚不清楚。在这里，我们表明 Sed5 和正向运输部分通过 MAPK 激酶 Hog1 调节 Hsp42 的磷酸化。这种磷酸化，特别是在残基 S215 处，使 Hsp42 与 Hsp104 解聚酶、聚集体清除、伴侣活性和聚集体隔离到 IPOD 和线粒体的共定位失效。此外，我们发现 Hsp42 在衰老细胞中过度磷酸化，导致严重的解聚失败。衰老细胞还表现出正向运输的延迟，这与聚集体清除缓慢和 Hsp42 的过度磷酸化一起，可以通过 Sed5 的过表达来抵消。我们假设，酵母衰老过程中适当的 PQC 的破坏可能部分是由于正向运输的延迟导致 Hsp42 的过度磷酸化。
