Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Cell Biol. 2022 Oct 3;221(10). doi: 10.1083/jcb.202202149. Epub 2022 Sep 7.
The chaperone-mediated sequestration of misfolded proteins into inclusions is a pivotal cellular strategy to maintain proteostasis in Saccharomyces cerevisiae, executed by small heat shock proteins (sHsps) Hsp42 and Btn2. Direct homologs of Hsp42 and Btn2 are absent in other organisms, questioning whether sequestration represents a conserved proteostasis strategy and, if so, which factors are involved. We examined sHsps from Escherchia coli, Caenorhabditis elegans, and humans for their ability to complement the defects of yeast sequestrase mutants. We show that sequestration of misfolded proteins is an original and widespread activity among sHsps executed by specific family members. Sequestrase positive C. elegans' sHsps harbor specific sequence features, including a high content of aromatic and methionine residues in disordered N-terminal extensions. Those sHsps buffer limitations in Hsp70 capacity in C. elegans WT animals and are upregulated in long-lived daf-2 mutants, contributing to lifespan extension. Cellular protection by sequestration of misfolded proteins is, therefore, an evolutionarily conserved activity of the sHsp family.
伴侣介导的错误折叠蛋白隔离到包涵体中是酵母细胞维持蛋白质平衡的关键策略，由小热休克蛋白（sHsp）Hsp42 和 Btn2 执行。其他生物中没有与 Hsp42 和 Btn2 直接同源的蛋白，这使得隔离是否代表一种保守的蛋白质平衡策略受到质疑，如果是这样，那么涉及哪些因素。我们研究了大肠杆菌、秀丽隐杆线虫和人类的 sHsp，以考察它们是否具有补充酵母隔离酶突变体缺陷的能力。我们表明，错误折叠蛋白的隔离是 sHsp 执行的一种原始且广泛存在的活动，由特定的家族成员执行。具有隔离酶活性的线虫 sHsp 具有特定的序列特征，包括无序 N 端延伸中高含量的芳香族和蛋氨酸残基。这些 sHsp 在 WT 线虫中缓冲了 Hsp70 能力的限制，并且在长寿的 daf-2 突变体中上调，有助于延长寿命。因此，错误折叠蛋白的隔离是 sHsp 家族的一种进化保守的活性，具有细胞保护作用。
