Considering the mechanism by which droplets of ALS-FTD-associated SQSTM1/p62 mutants cause pathology
Considering the mechanism by which droplets of ALS-FTD-associated SQSTM1/p62 mutants cause pathology
复制标题
考虑 ALS-FTD 相关 SQSTM1/p62 突变体液滴引起病理的机制
DOI：
10.1080/27694127.2022.2031380
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Komatsu M
中科院分区：
文献类型：
--
作者：
Ichimura Y;Komatsu M
在肌萎缩侧索硬化症（ALS）和额颞叶变性（FTD）中发现了大量SQSTM 1/p62的点突变。SQSTM 1与泛素化蛋白相互作用，经历液-液相分离，并且所产生的SQSTM 1-液滴通过巨自噬/自噬降解。SQSTM 1也是选择性自噬和抗氧化应激反应等过程的多信号中心。这些不同的功能是由整个蛋白质的多个结构域和区域调节的。由于SQSTM 1中的突变已在其整个基因中被鉴定，包括编码结构域和基序的区域，因此这些突变对疾病发作的影响被认为是复杂的。最近，我们彻底研究了LC 3相互作用区和KEAP 1相互作用区（氨基酸335-356）周围的7个突变如何影响SQSTM 1的自噬降解，抗氧化应激反应，KEAP 1-NFE 2L 2/Nrf 2通路以及SQSTM 1液滴的动力学。我们发现液滴内部流动性降低是所有突变体中唯一的共同缺陷，表明SQSTM 1液滴的定性变化与ALS-FTD之间存在联系。在这篇关于泪点的文章中，我们讨论了突变体SQSTM 1液滴内部流动性降低导致ALS-FTD病理的机制。
Large numbers of point mutations inSQSTM1/p62have been identified in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). SQSTM1 interacts with ubiquitinated proteins, undergoing liquid-liquid phase separation, and the resulting SQSTM1-droplets are degraded by macroautophagy/autophagy. SQSTM1 also serves as a multiple signaling hub for processes including selective autophagy and the anti-oxidative stress response. Such diverse functions are modulated by multiple domains and regions throughout the protein. Because mutations in SQSTM1 have been identified throughout its gene, including regions encoding the domains and motifs, the effects of these mutations on disease onset have been thought to be complicated. Recently, we thoroughly investigated how 7 mutations around the LC3-interacting region and KEAP1-interacting region (amino acids 335-356) affected autophagic degradation of SQSTM1, the anti-oxidative stress response, the KEAP1-NFE2L2/Nrf2 pathway, and the dynamics of SQSTM1 droplets. We found that reduced inner fluidity of the droplets is a unique, shared defect among all mutants, suggesting a link between qualitative changes in SQSTM1 liquid droplets and ALS-FTD. In this punctum article, we discuss the mechanism whereby reduced inner fluidity of mutant SQSTM1 droplets causes ALS-FTD pathology.