PUBLICATION

The selective autophagy receptors Optineurin and p62 are both required for zebrafish host resistance to mycobacterial infection

Authors
Zhang, R., Varela, M., Vallentgoed, W., Forn-Cuni, G., van der Vaart, M., Meijer, A.H.
ID
ZDB-PUB-190301-13
Date
2019
Source
PLoS pathogens   15: e1007329 (Journal)
Registered Authors
Meijer, Annemarie H., van der Vaart, Michiel, Varela, Monica, Zhang, Rui
Keywords
none
MeSH Terms
  • Disease Models, Animal
  • Phagosomes
  • Mycobacterium marinum/pathogenicity*
  • Transcription Factor TFIIIA/metabolism
  • Mycobacterium/pathogenicity
  • Zebrafish Proteins/metabolism
  • Animals, Genetically Modified
  • Zebrafish/metabolism
  • Sequestosome-1 Protein
  • Tuberculosis
  • Mycobacterium Infections, Nontuberculous/metabolism*
  • Host-Pathogen Interactions/physiology*
  • Animals
  • Autophagy/physiology
  • Humans
  • Ubiquitin
  • Mycobacterium Infections/metabolism
  • Macrophages
(all 18)
PubMed
30818338 Full text @ PLoS Pathog.
Abstract
Mycobacterial pathogens are the causative agents of chronic infectious diseases like tuberculosis and leprosy. Autophagy has recently emerged as an innate mechanism for defense against these intracellular pathogens. In vitro studies have shown that mycobacteria escaping from phagosomes into the cytosol are ubiquitinated and targeted by selective autophagy receptors. However, there is currently no in vivo evidence for the role of selective autophagy receptors in defense against mycobacteria, and the importance of autophagy in control of mycobacterial diseases remains controversial. Here we have used Mycobacterium marinum (Mm), which causes a tuberculosis-like disease in zebrafish, to investigate the function of two selective autophagy receptors, Optineurin (Optn) and SQSTM1 (p62), in host defense against a mycobacterial pathogen. To visualize the autophagy response to Mm in vivo, optn and p62 zebrafish mutant lines were generated in the background of a GFP-Lc3 autophagy reporter line. We found that loss-of-function mutation of optn or p62 reduces autophagic targeting of Mm, and increases susceptibility of the zebrafish host to Mm infection. Transient knockdown studies confirmed the requirement of both selective autophagy receptors for host resistance against Mm infection. For gain-of-function analysis, we overexpressed optn or p62 by mRNA injection and found this to increase the levels of GFP-Lc3 puncta in association with Mm and to reduce the Mm infection burden. Taken together, our results demonstrate that both Optn and p62 are required for autophagic host defense against mycobacterial infection and support that protection against tuberculosis disease may be achieved by therapeutic strategies that enhance selective autophagy.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ibl51
    Small Deletion
    ibl52
      Small Deletion
      ump2TgTransgenic Insertion
        zf155TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          1 - 1 of 1
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          Sequence Targeting Reagents
          Target Reagent Reagent Type
          optnCRISPR1-optnCRISPR
          optnMO5-optnMRPHLNO
          sqstm1CRISPR1-sqstm1CRISPR
          sqstm1MO1-sqstm1MRPHLNO
          1 - 4 of 4
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          Fish
          Antibodies
          Orthology
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          mCherryEFGmCherry
          1 - 2 of 2
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          Mapping