Lysosomal Degradation Is Required for Sustained Phagocytosis of Bacteria by Macrophages

Ching On Wong, Steven Gregory, Hongxiang Hu, Yufang Chao, Victoria E. Sepúlveda, Yuchun He, David Li-Kroeger, William E. Goldman, Hugo J. Bellen, Kartik Venkatachalam

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Clearance of bacteria by macrophages involves internalization of the microorganisms into phagosomes, which are then delivered to endolysosomes for enzymatic degradation. These spatiotemporally segregated processes are not known to be functionally coupled. Here, we show that lysosomal degradation of bacteria sustains phagocytic uptake. In Drosophila and mammalian macrophages, lysosomal dysfunction due to loss of the endolysosomal Cl transporter ClC-b/CLCN7 delayed degradation of internalized bacteria. Unexpectedly, defective lysosomal degradation of bacteria also attenuated further phagocytosis, resulting in elevated bacterial load. Exogenous application of bacterial peptidoglycans restored phagocytic uptake in the lysosomal degradation-defective mutants via a pathway requiring cytosolic pattern recognition receptors and NF-κB. Mammalian macrophages that are unable to degrade internalized bacteria also exhibit compromised NF-κB activation. Our findings reveal a role for phagolysosomal degradation in activating an evolutionarily conserved signaling cascade, which ensures that continuous uptake of bacteria is preceded by lysosomal degradation of microbes.

Original languageEnglish (US)
Pages (from-to)719-730.e6
JournalCell Host and Microbe
Volume21
Issue number6
DOIs
StatePublished - Jun 14 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Keywords

  • CLCN7
  • ClC-b
  • NF-κB
  • Relish
  • TRPML
  • cytosolic pattern recognition receptors
  • innate immunity
  • lysosomal degradation
  • phagocytosis
  • vesicular trafficking

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