Repurposing Herpesvirus Protein ORF57 to Inhibit TDP-43 Aggregation

ABSTRACT: The integrated stress response (ISR) is a major element of translation control. The ISR is beneficial in responding to acute stresses, but in human disease a chronic, persistent stress response can contribute to the disease process. Many studies manipulate the ISR by targeting just one protein. However, viral proteins have evolved to target many elements of this system. We examined the Herpesvirus protein ORF57, and determined the protein interaction network and identified that it binds to many proteins linked to the ISR. We show that expressing ORF57 in neuronal SH-SY5Y cells reduces the ISR, inhibiting the accumulation of G3BP1 positive stress granules. We then applied the ORF57 vector to examine the effects on aggregation of TDP-43, which accumulates in neurodegenerative diseases such as amyotrophic lateral sclerosis. We demonstrate that expressing ORF57 changes the dynamics of TDP-43 aggregation and granule formation, reducing the accumulation of aggregated TDP-43 by 36% and increasing the rate of dispersion of TDP-43 aggregates by 2.45-fold. These data suggest that viral proteins, such as ORF57, can be repurposed and applied to inhibit the types of chronic, persistent stress responses in mammalian cells that are associated with neurodegenerative diseases.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Benjamin Wolozin  

LAB HEAD: Benjamin Wolozin

PROVIDER: PXD039246 | Pride | 2024-08-09

REPOSITORIES: Pride