ASPL couples the assembly of stress granules with their VCP-mediated disassembly
Stress granules (SGs) are dynamic RNA-protein assemblies that form in response to cellular stress and must be efficiently disassembled to restore normal cell function. Valosin-containing protein (VCP), an enzyme implicated in neurodegenerative diseases, is essential for SG disassembly, but whether and how this process is coordinated with SG assembly remains unclear. Here, we identify the VCP cofactor, Alveolar soft part sarcoma locus (ASPL) as a key regulator linking SG assembly and disassembly. ASPL promotes SG assembly by facilitating biomolecular condensation of Ras guanosine triphosphatase-activating protein-binding protein (G3BP) and stabilizing its interactions with other SG proteins. ASPL also facilitates phosphorylation and activation of VCP by UNC-51-like kinases 1 and 2 (ULK1/2), enabling G3BP extraction and efficient SG disassembly. Pathogenic VCP mutations that disrupt ASPL binding impair SG disassembly, a defect rescued by phosphomimetic mutations or ASPL depletion. Our findings suggest that disruptions in the ASPL-VCP interaction uncouple SG assembly and disassembly, representing a potential mechanism underlying VCP-associated neurodegenerative diseases.
Authors
- Mitra S. Rana (ORCID: https://orcid.org/0000-0002-0915-8141)
- James Messing (ORCID: https://orcid.org/0000-0002-0915-3420)
- Ravi Kalathur (ORCID: https://orcid.org/0000-0002-4889-8003)
- Tharun Selvam Mahendran (ORCID: https://orcid.org/0000-0002-7536-1236)
- Joseph L. Basalla (ORCID: https://orcid.org/0009-0006-5444-344X)
- Xiujie Li-Harms
- Shondra M. Pruett‐Miller (ORCID: https://orcid.org/0000-0002-3793-585X)
- Gautam Pareek (ORCID: https://orcid.org/0000-0001-8430-9870)
- Mondira Kundu (ORCID: https://orcid.org/0000-0001-9946-2472)
- Anurag Singh (ORCID: https://orcid.org/0000-0002-8132-903X)
- Brian D. Freibaum (ORCID: https://orcid.org/0000-0001-5713-2088)
- Jingjun Lü (ORCID: https://orcid.org/0000-0002-2559-5923)
- Rachayata Dharmat (ORCID: https://orcid.org/0000-0001-6969-4459)
- Amanda Nourse (ORCID: https://orcid.org/0000-0003-4595-5321)
- Stanley Pounds (ORCID: https://orcid.org/0000-0002-9167-2114)
- Brian A. Maxwell (ORCID: https://orcid.org/0000-0002-0177-3991)
- Alexandre F. Carisey (ORCID: https://orcid.org/0000-0003-1326-2205)
- Yonghui Ni (ORCID: https://orcid.org/0000-0002-1127-1004)
- J. Paul Taylor (ORCID: https://orcid.org/0000-0002-5794-0349)
- Honghu Quan
- Priya R. Banerjee (ORCID: https://orcid.org/0000-0002-6169-1461)
- Bo Wang (ORCID: https://orcid.org/0000-0003-4182-0200)
- Dongfang Li (ORCID: https://orcid.org/0000-0003-0450-2780)
- Yong‐Dong Wang (ORCID: https://orcid.org/0000-0001-8751-9216)
- Hong Joo Kim (ORCID: https://orcid.org/0000-0002-9157-1612)
- J. Wu (ORCID: https://orcid.org/0009-0004-4253-0728)
Institutions
- St. Jude Children's Research Hospital (US)
- Xiamen University (CN)
- University at Buffalo, State University of New York (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-08
- DOI
- https://doi.org/10.1126/sciadv.ady3735
- Citations
- 2
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 1.61