DIAPH3 condensates formed by liquid-liquid phase separation act as a regulatory hub for stress-induced actin cytoskeleton remodeling
Ke Zhang,
Miaodan Huang,
Ang Li,
Jing Wen,
Lingli Yan,
Yunhao Li,
Liman Guo,
Kumaran Satyanarayanan Senthil,
Yangyang Zhou,
Guobing Chen,
Yong Liu,
Xiaofei Zhang,
Xiaoli Yao,
Dajiang Qin,
Huanxing Su
Affiliations
Ke Zhang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Miaodan Huang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Ang Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Jing Wen
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Lingli Yan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Yunhao Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Liman Guo
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
Kumaran Satyanarayanan Senthil
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Yangyang Zhou
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Guobing Chen
Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
Yong Liu
Laboratory of Neuroscience in Health and Disease Institute, Guangzhou First People’s Hospital School of Medicine, South China University of Technology, Guangzhou, China
Xiaofei Zhang
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
Xiaoli Yao
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Dajiang Qin
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Huanxing Su
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China; Corresponding author
Summary: Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to stress without first requiring nuclear feedback. In this study, we identify diaphanous-related formin 3 (DIAPH3), an actin nucleator, as a scaffold protein to initiate liquid-liquid phase separation (LLPS) and form abundant cytosolic phase-separated DIAPH3 granules (D-granules) in mammalian cells such as HeLa, HEK293, and fibroblasts under various stress conditions. Neither mRNAs nor known stress-associated condensate markers, such as G3BP1, G3BP2, and TIA1 for SGs and DCP1A for P-bodies, are detected in D-granules. Using overexpression and knockout of DIAPH3, pharmacological interventions, and optogenetics, we further demonstrate that stress-induced D-granules spatially sequester DIAPH3 within the condensation to inhibit the assembly of actin filaments in filopodia. This study reveals that D-granules formed by LLPS act as a regulatory hub for actin cytoskeletal remodeling in response to stress.
