Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:58 |
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| Enthalten in: |
Developmental cell - 58(2023), 22 vom: 20. Nov., Seite 2495-2509.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Teo, Qi Wen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.12.2023 Date Revised 09.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.devcel.2023.08.013 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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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| 700 | 1 | |a Stancheva, Viktoriya |e verfasserin |4 aut | |
| 700 | 1 | |a Hachim, Asmaa |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Huibin |e verfasserin |4 aut | |
| 700 | 1 | |a Siu, Lewis |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Yun |e verfasserin |4 aut | |
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| 700 | 1 | |a Ulferts, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Sanyal, Sumana |e verfasserin |4 aut | |
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