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@ARTICLE{Metz:127126,
      author       = {P. Metz and A. Chiramel and L. Chatel-Chaix and G. Alvisi
                      and P. Bankhead and R. Mora-Rodriguez$^*$ and G. Long and A.
                      Hamacher-Brady$^*$ and N. R. Brady$^*$ and R.
                      Bartenschlager$^*$},
      title        = {{D}engue {V}irus {I}nhibition of {A}utophagic {F}lux and
                      {D}ependency of {V}iral {R}eplication on {P}roteasomal
                      {D}egradation of the {A}utophagy {R}eceptor p62.},
      journal      = {Journal of virology},
      volume       = {89},
      number       = {15},
      issn         = {1098-5514},
      address      = {Baltimore, Md.},
      publisher    = {Soc.},
      reportid     = {DKFZ-2017-03152},
      pages        = {8026 - 8041},
      year         = {2015},
      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 during DENV infection, 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
                      them TOR inhibitor Torin1.We found that DENV induced 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 to AV formation and reduced AV
                      degradation capacity. During late infection AV levels
                      increased as a result of inefficient fusion of
                      autophagosomes with lysosomes. In addition, endolysosomal
                      trafficking was suppressed, while lysosomal activities were
                      increased.We further determined that DENV infection
                      progressively reduced levels of the autophagy receptor
                      SQSTM1/p62 via proteasomal degradation. Importantly, stable
                      overexpression of p62 significantly suppressed DENV
                      replication, suggesting a novel role for p62 as a viral
                      restriction factor. Overall, our findings indicate that in
                      the course of DENV infection, autophagy shifts from a
                      supporting to an antiviral role, which is countered by
                      DENV.Autophagic flux is a dynamic process starting with the
                      formation of autophagosomes and ending with their
                      degradation after fusion with lysosomes. Autophagy impacts
                      the replication cycle of many viruses. However, thus far the
                      dynamics of autophagy in case of Dengue virus (DENV)
                      infections has not been systematically quantified.
                      Therefore, we used high-content, imaging-based flow
                      cytometry to quantify autophagic flux and endolysosomal
                      trafficking in response to DENV infection. We report that
                      DENV induced an initial activation of autophagic flux,
                      followed by inhibition of general and specific autophagy.
                      Further, lysosomal activity was increased, but endolysosomal
                      trafficking was suppressed confirming the block of
                      autophagic flux. Importantly, we provide evidence that p62,
                      an autophagy receptor, restrict DENV replication and was
                      specifically depleted in DENV-infected cells via increased
                      proteasomal degradation. These results suggest that during
                      DENV infection autophagy shifts from a proviral to an
                      antiviral cellular process, which is counteracted by the
                      virus.},
      keywords     = {Adaptor Proteins, Signal Transducing (NLM Chemicals) /
                      SQSTM1 protein, human (NLM Chemicals) / Sequestosome-1
                      Protein (NLM Chemicals)},
      cin          = {B190 / F170},
      ddc          = {570},
      cid          = {I:(DE-He78)B190-20160331 / I:(DE-He78)F170-20160331},
      pnm          = {316 - Infections and cancer (POF3-316)},
      pid          = {G:(DE-HGF)POF3-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26018155},
      pmc          = {pmc:PMC4505648},
      doi          = {10.1128/JVI.00787-15},
      url          = {https://inrepo02.dkfz.de/record/127126},
}