Dengue virus inhibition of autophagic flux and dependency of viral replication on proteasomal degradation of the autophagy receptor p62

Philippe Metz, Abhilash Chiramel, Laurent Chatel-Chaix, Gualtiero Alvisi, Peter Bankhead, Rodrigo Mora-Rodríguez, Gang Long, Anne Hamacher-Brady, Nathan R. Brady, Ralf Bartenschlager

Research output: Contribution to journalArticlepeer-review

Abstract

Autophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV), several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question and gain insight into the role of autophagy duringDENVinfection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or themTORinhibitor Torin1.Wefound thatDENVinduced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block toAVformation and reducedAVdegradation capacity. During late infectionAVlevels increased as a result of inefficient fusion of autophagosomes with lysosomes. In addition, endolysosomal trafficking was suppressed, while lysosomal activities were increased.Wefurther determined thatDENVinfection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable overexpression of p62 significantly suppressedDENVreplication, suggesting a novel role for p62 as a viral restriction factor. Overall, our findings indicate that in the course ofDENVinfection, autophagy shifts from a supporting to an antiviral role, which is countered by DENV.

Original languageEnglish (US)
Pages (from-to)8026-8041
Number of pages16
JournalJournal of virology
Volume89
Issue number15
DOIs
StatePublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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