KSHV-ORF57 inhibits stress granule assembly and may be a novel biotherapeutic for neurodegenerative diseases
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Abstract
Open reading frame 57 (ORF57), a protein found in the genome of Kaposi’s Sarcoma Virus (KSV), has been shown to interact with protein kinase R (PKR) and inhibit its activation by blocking PKRs interaction with PKR activating protein (PACT). PKR activation is a key step in stress granule (SG) assembly, a pathway implicated in the pathology of many neurodegenerative diseases, including Alzheimer’s Disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Expression of ORF57 in human neuroblastoma cells (SH-SY5Y) shows promise as an inhibitor of this pathway. ORF57 expression in SH-SY5Y cells showed decreases in SG-associated protein aggregates and phosphorylation of eukaryotic initiation factor 2𝛂 (eIF2𝛂), a necessary phosphorylation event upstream of SG assembly when treated with oxidative stress. ORF57 expression also shows increased translation and decreased apoptosis when cells are exposed to oxidative stress. These changes indicate a potential role of ORF57 as a stress granule pathway inhibitor. To further investigate ORF57’s potential as a biotherapeutic for neurodegenerative disease, and specifically ALS, ORF57 was expressed in a cell line overexpressing cytoplasmic TDP43 (SH-SY5Y TDP43 𝛥NLS). These cells expressing ORF57 under stress conditions showed decreases in SG-associated protein aggregates and phosphorylation of eIF2𝛂. SH-SY5Y TDP43 𝛥NLS cells expressing ORF57 under stress also showed an increase in the soluble fraction of TDP43. Taken together, ORF57 shows promise as a PKR inhibitor with potential for treating SG-associated neurodegenerative pathologies.