Journal Article

Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation

Li, Yichen, Zhang Shengnan, Li, Dan, Gui Xinrui, Wang Chuchu, Liu, Cong, Gu Jinge, Long Houfang, Liu, Zhijun, Liu Zhenying, Tong Yilun, Li, Ying, He, Lin, Zhao, Chunyu, Lu Jinxia

2020

Overview

Protein phase separation drives the assembly of membraneless organelles, but little is known about how these membraneless organelles are maintained in a metastable liquid- or gel-like phase rather than proceeding to solid aggregation. Here, we find that human small heat-shock protein 27 (Hsp27), a canonical chaperone that localizes to stress granules (SGs), prevents FUS from undergoing liquid−liquid phase separation (LLPS) via weak interactions with the FUS low complexity (LC) domain. Remarkably, stress-induced phosphorylation of Hsp27 alters its activity, leading Hsp27 to partition with FUS LC to preserve the liquid phase against amyloid fibril formation. NMR spectroscopy demonstrates that Hsp27 uses distinct structural mechanisms for both functions. Our work reveals a fine-tuned regulation of Hsp27 for chaperoning FUS into either a polydispersed state or a LLPS state and suggests an essential role for Hsp27 in stabilizing the dynamic phase of stress granules.The chaperone Hsp27 prevents FUS from undergoing liquid–liquid phase separation until stress-induced phosphorylation causes Hsp27 to partition with FUS to preserve the liquid phase against amyloid fibril formation.

• Publisher: Nature Publishing Group
• Subject: Amyloid / Chaperones / Granular materials / Heat shock proteins / Hsp27 protein / Liquid phases / Magnetic resonance spectroscopy / NMR / NMR spectroscopy / Nuclear magnetic resonance / Organelles / Partitions / Phase separation / Phosphorylation