Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey.
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey; Omenn-Darling Bioengineering Institute, Princeton University, Princeton, New Jersey; Howard Hughes Medical Institute, Chevy Chase, Maryland.
Biophys J. 2024 Jun 4;123(11):1404-1413. doi: 10.1016/j.bpj.2023.10.009. Epub 2023 Oct 13.
Protein aggregates, formed from the assembly of aberrant, misfolded proteins, are a hallmark of neurodegenerative diseases. Disease-associated aggregates such as mutant Huntingtin polyQ inclusions, are typically enriched in p62/SQSTM1, an oligomeric protein that binds to and sequesters aberrant proteins. p62 has been suggested to sequester proteins through formation of liquid-like biomolecular condensates, but the physical mechanisms by which p62 condensates may regulate pathological protein aggregation remain unclear. Here, we use a light-inducible biomimetic condensate system to show that p62 condensates enhance coarsening of mutant polyQ aggregates through interface-mediated sequestration, which accelerates polyQ accumulation into larger aggregates. However, the resulting large aggregates accumulate polyubiquitinated proteins, which depletes free p62, ultimately suppressing further p62 condensation. This dynamic interplay between interface-mediated coarsening of solid aggregates and downstream consequences on the phase behavior of associated regulatory proteins could contribute to the onset and progression of protein aggregation diseases.
蛋白质聚集体是由异常折叠的蛋白质组装而成的，是神经退行性疾病的一个标志。与疾病相关的聚集体，如突变亨廷顿蛋白 polyQ 包涵体，通常富含 p62/SQSTM1，这是一种寡聚蛋白，能够与异常蛋白质结合并将其隔离。p62 被认为通过形成液态生物分子凝聚物来隔离蛋白质，但 p62 凝聚物调节病理性蛋白质聚集的物理机制尚不清楚。在这里，我们使用光诱导的仿生凝聚物系统表明，p62 凝聚物通过界面介导的隔离增强了突变 polyQ 聚集体的粗化，从而加速了 polyQ 积累到更大的聚集体中。然而，由此产生的大聚集体积累了多聚泛素化蛋白质，耗尽了游离的 p62，最终抑制了 p62 的进一步凝聚。这种固态聚集体界面介导的粗化与相关调节蛋白相态行为的下游后果之间的动态相互作用，可能导致蛋白质聚集疾病的发生和进展。
