ASPL’s Twin Position in Stress Granule Meeting and Disassembly

Stress granules are droplet-like protein hubs that quickly protect fragile RNA from mobile stresses corresponding to toxins. VCP is a protein important for breaking apart stress granules and has been linked to neurodegenerative ailments. However, VCP has a protein companion, ASPL, whose function has been unclear till now. Scientists at St. Jude Children’s Research Hospital found that ASPL regulates stress granule disassembly by facilitating VCP phosphorylation. They additionally discovered ASPL facilitates stress granule meeting impartial of VCP by stabilizing interactions amongst core stress granule proteins. The findings, revealed at the moment in Science Advances, present key perception into the hyperlink between stress granules and neurodegenerative illness.

Stress granules are fastidiously regulated, forming solely throughout stresses, corresponding to warmth or an infection, and disassembling as soon as the stress is resolved. Mutations in proteins corresponding to VCP can derail this cycle, resulting in the irregular accumulation of proteins, which causes a situation known as multisystem proteinopathy. 

“VCP mutations are found in patients with multisystem proteinopathy, which includes amyotrophic lateral sclerosis, frontotemporal dementia and Paget’s disease of bone,” stated corresponding writer Mondira Kundu, MD, PhD, St. Jude Department of Cell & Molecular Biology. “While VCP has multiple functions, its ability to disassemble RNA-protein assemblies, such as stress granules, is impaired by disease-causing mutations.” 

ASPL, VCP and ULK work collectively to interrupt up stress granules

After discovering that VCP and ASPL work together with ULK, one other protein concerned in regulating stress granule disassembly, Kundu and her staff determined to dig into the connection. “ULK regulates stress granule dynamics, so we wondered whether ASPL was also involved through its interaction with either ULK or VCP,” Kundu stated. 

The staff discovered that ASPL was required for ULK to hold out its perform, which is VCP’s phosphorylation (addition of a phosphate group). Phosphorylation triggers VCP to take away the keystone stress granule protein G3BP from stress granules, inflicting them to interrupt up. Without VCP phosphorylation, the stress granules persist. 

These findings are in keeping with what happens throughout multisystem proteinopathy. “Certain disease-causing VCP mutants don’t interact as well with ASPL and ULK, and also have stress granule disassembly defects,” Kundu defined. “Restoring VCP phosphorylation restores disassembly, suggesting that these mutants decrease VCP binding to ASPL and subsequent phosphorylation by ULK.”

ASPL goes solo to assist assemble stress granules

In a stunning flip, the researchers additionally noticed that ASPL overexpression sharply elevated stress granule formation. Removing ASPL resulted in smaller and slower-forming stress granules. This advised that ASPL performs a task in stress granule meeting. But this perform of ASPL didn’t contain VCP, so the researchers got down to tease aside how ASPL may promote the formation of stress granules by itself, impartial of VCP.

“We created cell lines that express a version of ASPL that cannot bind VCP and found that these cells had no problems with granule assembly but did a poor job with disassembly,” Kundu stated. “This showed us that ASPL promoted stress granule assembly, and ASPL’s interaction with VCP is important for efficient disassembly.”

The researchers found this mechanism was tied to G3BP. “Removing ASPL decreased interactions between stress granule components, lowering the probability of stress granules being formed,” Kundu defined. “Fluorescence recovery experiments suggested that ASPL alters G3BP’s interactions with other proteins, making the network less stable without ASPL.”

These findings add nuance to scientists’ understanding of stress granule regulation, increasing on the checks and balances that govern the method and highlighting potential pathways to illness. “A key question is whether disrupting the ASPL-VCP interaction, specifically through ASPL, can mimic multisystem proteinopathy,” Kundu stated. “That’s the biggest missing link currently, and one we are exploring.”

Reference: Pareek G, Li D, Wang B, et al. ASPL {couples} the meeting of stress granules with their VCP-mediated disassembly. Science Advances. 2025;11(41):eady3735. doi:10.1126/sciadv.ady3735

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