Read this new publication from HKU-Pasteur by Qi Wen Teo with Sumana Sanyal investigating cholesterol flux and virus infections.
Teo et al. report that Usp25, a deubiquitylase, is able to restrict virus infection by stabilizing the Erlin1/2 complex, which in turn regulates intracellular cholesterol levels. Absence of Usp25 drives Erlin1/2 degradation and increased cholesterol flux, providing a conducive
environment for the assembly and secretion of pathogenic viruses.
- Usp25 deficiency increases susceptibility to pathogenic RNA viruses
- Usp25 stabilizes the Erlin1/2 complex in virus-infected cells
- Erlin1/2 negatively regulates the SREBP2 pathway to block cholesterol synthesis
- Reduced cholesterol levels can trigger TLR3 dependent inflammatory responses
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 Usp25C178S cells, activating Srebp2, with increased cholesterol flux and attenuated TLR3 dependent responses. Our study therefore defines the function of a deubiquitylase that serves to restrict a range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses.
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