Rotavirus-NSP5 interacts with and hijacks host ATP citrate lyase to viroplasms, enhancing lipid biosynthesis for facilitating rotavirus infection.
ACLY appears to play a crucial role in rotavirus infection, and its inhibition may reduce viral replication and improve intestinal health in animal models.
Where it sits
this study against the rest of the snap-8 corpusSummary and findings
This study examined the interaction between rotavirus NSP5 and host proteins, particularly ATP citrate lyase (ACLY), during rotavirus infection. The researchers identified 128 host proteins interacting with NSP5 and noted that ACLY phosphorylation increased following infection. Inhibition of ACLY reduced viral titers and improved histopathology in BALB/c suckling mice.
Abstract
Rotavirus (RV) replication occurs within viroplasms (VMs) and is initiated by two RV non-structural proteins NSP2 and NSP5. Viruses exploit host cellular components for their replication and assembly; however, information on the roles of host proteins in VM dynamics and RV replication is limited. Thus, in the current study, we used proteomics to identify host proteins that interact with NSP5 during RV infection to delineate their role in virus replication. A large number of host proteins (n = 128) were found to interact with NSP5, and Gene Ontology enrichment analysis revealed the enrichment of various metabolic processes during RV infection. One of the essential host proteins, ATP citrate lyase (ACLY), which is involved in the de novo lipid synthesis pathway, was found to interact with C-terminal region of RV-NSP5 and colocalize within VMs. Following RV infection, the serine 455 phosphorylation of ACLY was induced, suggesting increased enzymatic activation. This correlates with enhanced lipid droplet production via increased acetyl-coenzyme A expression levels, which in turn supports VM formation. The ACLY inhibitors SB204990 or hydroxycitric acid tripotassium hydrate significantly reduced RV-infection in vitro. This anti-rotaviral effect of drug was further validated in BALB/c suckling mice by measuring viral protein expression and viral titers. In the presence of ACLY inhibitor, reduced viral titers, reduced viral protein expression, and improved small intestinal histopathology were observed. These findings suggest a protective effect of drugs against RV infection in vivo and highlight ACLY as a potential anti-rotaviral target for the development of new therapeutics.
Background
This paper addresses the role of host proteins in rotavirus replication, specifically focusing on the interaction between rotavirus NSP5 and ATP citrate lyase (ACLY). Prior knowledge indicates that viruses utilize host cellular components for replication, but the specific roles of these proteins in viroplasm dynamics and rotavirus infection have been inadequately explored. Understanding these interactions could provide insights into potential therapeutic targets for rotavirus infections.
Methods
The study utilized proteomics to identify host proteins interacting with NSP5 during rotavirus infection. The population included in vitro models and BALB/c suckling mice. The primary outcome measures were the effects of ACLY inhibitors on viral titers and protein expression, as well as histopathological changes in the small intestine.
Results
The study found that 128 host proteins interacted with NSP5, with ACLY being a significant player in lipid biosynthesis. Following rotavirus infection, phosphorylation of ACLY at serine 455 was observed, indicating increased activity. The use of ACLY inhibitors resulted in a significant reduction in rotavirus infection in vitro, and in vivo studies showed reduced viral titers and improved intestinal histopathology.
Interpretation
These findings suggest that ACLY plays a crucial role in rotavirus infection, supporting previous literature on the importance of lipid metabolism in viral replication. While the statistical significance of the findings is noted, the clinical relevance remains uncertain due to the reliance on animal models and in vitro studies. The potential for ACLY as a therapeutic target is promising but requires further investigation in human studies.
Key findings
- n=128 host proteins identified interacting with NSP5.
- ACLY phosphorylation at serine 455 was induced following RV infection.
- ACLY inhibitors SB204990 or hydroxycitric acid tripotassium hydrate significantly reduced RV infection in vitro.
- In BALB/c suckling mice, reduced viral titers and reduced viral protein expression were observed with ACLY inhibitor.
- Improved small intestinal histopathology was noted in the presence of ACLY inhibitor.
Limitations
- primarily in vitro and animal model evidence
- small sample size in animal studies
- potential translational limitations to human conditions
- no long-term follow-up reported