Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Mol Cell. 2023 Sep 7;83(17):3140-3154.e7. doi: 10.1016/j.molcel.2023.07.018. Epub 2023 Aug 11.
Peroxiredoxins (Prdxs) utilize reversibly oxidized cysteine residues to reduce peroxides and promote HO signal transduction, including HO-induced activation of P38 MAPK. Prdxs form HO-induced disulfide complexes with many proteins, including multiple kinases involved in P38 MAPK signaling. Here, we show that a genetically encoded fusion between a Prdx and P38 MAPK is sufficient to hyperactivate the kinase in yeast and human cells by a mechanism that does not require the HO-sensing cysteine of the Prdx. We demonstrate that a P38-Prdx fusion protein compensates for loss of the yeast scaffold protein Mcs4 and MAP3K activity, driving yeast into mitosis. Based on our findings, we propose that the HO-induced formation of Prdx-MAPK disulfide complexes provides an alternative scaffold and signaling platform for MAPKK-MAPK signaling. The demonstration that formation of a complex with a Prdx is sufficient to modify the activity of a kinase has broad implications for peroxide-based signal transduction in eukaryotes.
过氧化物还原酶（Prdxs）利用可还原的半胱氨酸残基来还原过氧化物，并促进 HO 信号转导，包括 HO 诱导的 P38 MAPK 激活。Prdxs 与许多蛋白质形成 HO 诱导的二硫键复合物，包括参与 P38 MAPK 信号转导的多种激酶。在这里，我们表明，Prdx 与 P38 MAPK 之间的遗传编码融合足以通过一种不依赖于 Prdx 的 HO 感应半胱氨酸的机制在酵母和人类细胞中过度激活激酶。我们证明，P38-Prdx 融合蛋白可以补偿酵母支架蛋白 Mcs4 和 MAP3K 活性的丧失，从而驱动酵母进入有丝分裂。基于我们的发现，我们提出 HO 诱导的 Prdx-MAPK 二硫键复合物的形成提供了 MAPKK-MAPK 信号转导的替代支架和信号平台。证明与 Prdx 形成复合物足以修饰激酶的活性，这对真核生物中基于过氧化物的信号转导具有广泛的意义。
