Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication
Recommended Citation
Hafner A, Meurs N, Garner A, Azar E, Kannan A, Passalacqua KD, Nagrath D, and Wobus CE. Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication. PLoS Pathog 2024; 20(7):e1011909.
Document Type
Article
Publication Date
7-1-2024
Publication Title
PLoS Pathog
Abstract
Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.
Medical Subject Headings
Norovirus; Virus Replication; Mice; Animals; Viral Nonstructural Proteins; Glutamine; Caliciviridae Infections; Macrophages; Humans; Glutaminase; Glycolysis; RAW 264.7 Cells
PubMed ID
38976719
Volume
20
Issue
7
First Page
1011909
Last Page
1011909
