Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection

Cell Host Microbe. 2017 May 10;21(5):637-649.e6. doi: 10.1016/j.chom.2017.04.008.

Abstract

Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins that are differentially phosphorylated following fungal ingestion by macrophages, thereby indicating global reprogramming of host kinase signaling. Notably, phagocytosis of the pathogen activates the host autophagy initiation complex (AIC) and the upstream regulatory components LKB1 and AMPKα, which regulate autophagy induction through their kinase activities. Deletion of Prkaa1, the gene encoding AMPKα1, in monocytes results in resistance to fungal colonization of mice. Finally, the recruitment of AIC components to nascent Cryptococcus-containing vacuoles (CnCVs) regulates the intracellular trafficking and replication of the pathogen. These findings demonstrate that host AIC regulatory networks confer susceptibility to infection and establish a proteomic resource for elucidating host mechanisms that regulate fungal intracellular parasitism.

Keywords: AMPKα; Cryptococcus neoformans; autophagy initiation complex; fungal pathogen; host factors; host-pathogen interaction; kinase signaling; phagocytosis; phosphoproteomics; proteomics.

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Biological Transport / physiology
  • Cell Line
  • Coxiella burnetii / pathogenicity
  • Cryptococcosis / immunology*
  • Cryptococcosis / microbiology
  • Cryptococcus neoformans / genetics*
  • Cryptococcus neoformans / growth & development
  • Cryptococcus neoformans / metabolism
  • Cryptococcus neoformans / pathogenicity*
  • Disease Models, Animal
  • Female
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology*
  • Host-Pathogen Interactions / physiology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • Phagocytosis
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteomics
  • RAW 264.7 Cells
  • Signal Transduction / physiology*
  • Vacuoles / microbiology
  • Virulence / genetics*
  • Virulence / physiology

Substances

  • ATG13 protein, mouse
  • Apoptosis Regulatory Proteins
  • Fungal Proteins
  • Stk11 protein, mouse
  • AMPK alpha1 subunit, mouse
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • Ulk1 protein, mouse
  • AMP-Activated Protein Kinases