Science for Life Laboratory and Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrhenius väg 20C, Stockholm, 10691, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, 17165, Solna, Sweden.
Nat Commun. 2023 Nov 22;14(1):7636. doi: 10.1038/s41467-023-43385-x.
The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that high levels of LarA cause growth inhibition in a Lon-dependent manner and that Lon-mediated degradation of LarA itself ensures low LarA levels in the absence of stress. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand in response to protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.
Lon 蛋白酶是一种高度保守的蛋白降解机器，在来自生命三个域的细胞中具有关键的调节和蛋白质质量控制功能。在这里，我们报告了一种α-变形菌热休克蛋白 LarA 的发现，它作为一种专门的 Lon 调节剂发挥作用。我们表明，LarA 在蛋白质毒性应激开始时积累，并通过其 C 末端的五个氨基酸序列别构激活 Lon 催化的一大组底物的降解。此外，我们发现高水平的 LarA 以 Lon 依赖性方式引起生长抑制，并且 Lon 介导的 LarA 自身的降解确保在没有应激的情况下 LarA 水平较低。我们认为，暂时的 LarA 依赖性 Lon 激活有助于满足对蛋白质展开应激的增加的蛋白水解需求。我们的研究定义了一种保守蛋白酶与热休克蛋白的调节相互作用，作为蛋白酶活性如何在不断变化的环境条件下进行调整的范例。
