基于SQSTM1/p62的聚集体样诱导结构的聚集性决定了对PARP-1依赖性细胞死亡的敏感性。

Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos.

作者信息

Hamano Shuhei, Noguchi Takuya, Asai Yukino, Ito Ryo, Komatsu Ryuto, Sato Tetsu, Inoue Aya, Maruyama Tomoe, Kudo Tada-Aki, Hirata Yusuke, Shindo Sawako, Uchida Yasuo, Hwang Gi-Wook, Matsuzawa Atsushi

机构信息

Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

出版信息

Cell Death Discov. 2024 Feb 12;10(1):74. doi: 10.1038/s41420-024-01838-2.

DOI:10.1038/s41420-024-01838-2

PMID:38346947

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10861449/

Abstract

Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.

摘要

聚（ADP - 核糖）聚合酶 -1（PARP -1）的过度激活会引发一种非经典形式的程序性细胞死亡（PCD），称为parthanatos，但对其诱导机制尚未完全了解。我们最近证明，由自噬受体SQSTM1/p62和K48连接的多聚泛素化蛋白组成的聚集体样诱导结构（ALIS，基于p62的ALIS）介导parthanatos。在本研究中，我们鉴定出D1多巴胺受体激动剂YM435是一种独特的parthanatos抑制剂，它作为基于p62的ALIS的解聚剂发挥作用。我们发现YM435在结构上降低了ALIS的聚集性，进而增加了其亲水性和流动性，从而防止parthanatos。此外，多巴胺和多巴胺前体L - DOPA也通过降低ALIS的聚集性来防止parthanatos。这些观察结果共同表明，基于p62的ALIS的聚集性决定了对parthanatos的敏感性，而降低聚集性的YM435的药理特性可能适用于治疗parthanatos相关疾病，如神经退行性疾病的治疗药物。