The SARS-CoV-2 N protein disrupts G3BP1 function and alters lipid metabolism in COVID-19 pathogenesis.

The SARS-CoV-2 nucleocapsid (N) protein plays a pivotal role in disrupting host cellular processes by interfering with G3BP1, a key stress granule protein involved in RNA binding and metabolic regulation. Using RNA immunoprecipitation coupled with nanopore sequencing, we found that the N protein significantly alters the RNA interactome of G3BP1, particularly reducing binding to transcripts involved in fatty acid metabolism, such as ACOT12, PLIN4, GPX1, and ACADS. This disruption leads to dysregulation of lipid homeostasis and stress granule assembly, suggesting a strategy of the virus to reprogram host metabolism for its advantage. We also found that the N protein of the Wuhan strain exhibits stronger G3BP1 binding than that of the Omicron variant, potentially contributing to differences in pathogenicity. Mendelian randomization identified dihomolinoleate (20:2n6), an omega-6 polyunsaturated fatty acid, as a protective factor against severe COVID-19, while 4-androsten-3beta,17beta-diol disulfate, a steroid hormone metabolite, was associated with increased disease severity. These findings highlight the critical role of lipid metabolism in COVID-19 pathogenesis. The upregulation of the dihomolinoleate metabolic pathway genes in COVID-19 patients further underscores the importance of metabolic reprogramming during infection.