biostudies-literatureTeo QWResearch Grants Council, University Grants CommitteeThe Francis Crick InstituteHealth and Medical Research FundInnovation and Technology CommissionWellcome Trust2495-2509.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC10914638biostudies-literatureUnknown58(22)Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25^-/- or Usp25^C178S cells, activating Srebp2, with Developmental cellUsp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.PMC10914638CC208717113019220776/Z/20/Z223107/Z/21/Z19180912Stancheva VTeo QWHo JHeunis TUlferts RLv HHachim ASiu LWong HHMok CKPLan YSanyal SfalseUsp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25^-/- or Usp25^C178S cells, activating Srebp2, with 2023-01-01T00:00:00Z2023 Nov2026-06-09T07:09:58.629Z2026-06-09T03:12:20.894ZS-EPMC109146383768363010.1016/j.devcel.2023.08.013