Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation

Cell Host Microbe. 2012 Mar 15;11(3):264-76. doi: 10.1016/j.chom.2012.01.018.

Abstract

Phagocytosis and autophagy are two important and related arms of the host's first-line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions as part of a Beclin-1-Vps34-containing autophagy complex. We report that Rubicon is also an essential, positive regulator of the NADPH oxidase complex. Upon microbial infection or Toll-like-receptor 2 (TLR2) activation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating its phagosomal trafficking to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Consequently, ectopic expression or depletion of Rubicon profoundly affected ROS, inflammatory cytokine production, and subsequent antimicrobial activity. Rubicon's actions in autophagy and in the NADPH oxidase complex are functionally and genetically separable, indicating that Rubicon functions in two ancient innate immune machineries, autophagy and phagocytosis, depending on the environmental stimulus. Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Autophagy-Related Proteins
  • Cells, Cultured
  • Cytokines / metabolism
  • Enzyme Activation
  • Enzyme Stability
  • Female
  • Gram-Positive Bacterial Infections / enzymology*
  • Gram-Positive Bacterial Infections / immunology
  • Gram-Positive Bacterial Infections / metabolism
  • Humans
  • Immunity, Innate
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Listeria monocytogenes
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microbial Viability
  • Mycobacterium bovis
  • NADPH Oxidase 2
  • NADPH Oxidases / metabolism*
  • Phagocytosis
  • Phagosomes / enzymology
  • Protein Binding
  • Protein Transport
  • Reactive Oxygen Species / metabolism
  • Toll-Like Receptors / metabolism
  • Toll-Like Receptors / physiology*

Substances

  • Autophagy-Related Proteins
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Reactive Oxygen Species
  • Toll-Like Receptors
  • rundataxin protein, human
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • CYBA protein, human