Alphaviral Capsid Proteins Inhibit Stress Granule Assembly via Competitive RNA Binding With G3BP1

Yun Zhang; Yi Liu; Zhiying Yao; Haolong Lai; Xiaoxin Chen; Ziqiu Wang; Yiqiong Bao; Tingting Li; Xiaoming Zhou; Xiabin Chen; Peiguo Yang; Zai-Fu Yao

doi:10.1002/advs.202517009

Alphaviral Capsid Proteins Inhibit Stress Granule Assembly via Competitive RNA Binding With G3BP1

Yun Zhang, Yi Liu, Zhiying Yao, Haolong Lai, Xiaoxin Chen, Ziqiu Wang, Yiqiong Bao, Tingting Li, Xiaoming Zhou, Xiabin Chen, …

Advanced science, Vol.13(20), pp.e17009-n/a

01/04/2026

: https://doi.org/10.1002/advs.202517009

: 41591303

: WOS:001670036400001

Chemistry

Chemistry, Multidisciplinary

Materials Science

Materials Science, Multidisciplinary

Nanoscience & Nanotechnology

Physical Sciences

Science & Technology

Science & Technology - Other Topics

Technology

Viral infection is one of the conditions that induce stress granule (SG) formation, a cellular defense mechanism that exerts antiviral effects. To counteract this host response, viruses have evolved a broad spectrum of strategies to inhibit SG formation. However, the molecular mechanisms underlying SG inhibition remain poorly understood. The nucleocapsid proteins play a critical role in virus replication and host interaction. Here, using Semliki Forest Virus (SFV) as a model, we uncover the function of the alphavirus nucleocapsid in SG inhibition. This inhibitory function depends on oligomerization mediated by an N-terminal alpha-helix and with a positively charged intrinsically disordered region (IDR). We show that SFV capsid directly competes with G3BP1 for RNA binding, thereby disrupting G3BP1-RNA liquid-liquid phase separation (LLPS) in vitro and SG assembly in cells. This mechanism is conserved across the alphavirus family but is not shared by the nucleocapsid of SARS-CoV-2 or other endemic viruses examined. Notably, expression of a peptide from SFV capsid is sufficient to inhibit SG formation induced by Amyotrophic Lateral Sclerosis (ALS)-associated mutations, suggesting potential therapeutic applications. Our findings reveal mechanistic insight into SG modulation by the viral capsid protein and provide a possible bioengineering tool for probing SG dynamics in health and disease.

(1)

url

https://doi.org/10.1002/advs.202517009

Published (Version of record)

: Alphaviral Capsid Proteins Inhibit Stress Granule Assembly via Competitive RNA Binding With G3BP1
: Yun Zhang - Hangzhou Normal University
Yi Liu - Westlake University
Zhiying Yao - Westlake University
Haolong Lai - Westlake University
Xiaoxin Chen - Hangzhou Normal University
Ziqiu Wang - Westlake University
Yiqiong Bao - Peking University
Tingting Li - Peking University
Xiaoming Zhou - Westlake University
Xiabin Chen - Hangzhou Normal University
Peiguo Yang - Westlake University
Zai-Fu Yao - 竹師教育學院
: Wiley
: 26
: WU2022A002 / Center of Synthetic Biology and Integrated Bioengineering of Westlake University 2025JCXK02 / Interdisciplinary Research Project of Hangzhou Normal University 2025M772812 / China Postdoctoral Science Foundation 2025YFC3409700 / National Key Research and Development Project of China; National Key Research & Development Program of China 32470733; 32170696 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC)
: Journal article
: 01/04/2026
: Advanced science, Vol.13(20), pp.e17009-n/a
: English