TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation

Immunity. 2012 Aug 24;37(2):223-34. doi: 10.1016/j.immuni.2012.04.015.

Abstract

Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy / immunology*
  • Autophagy-Related Protein 7
  • Green Fluorescent Proteins
  • HeLa Cells
  • Heat-Shock Proteins / immunology
  • Heat-Shock Proteins / metabolism
  • Humans
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Mycobacterium bovis / immunology
  • Phagosomes / drug effects
  • Phagosomes / immunology
  • Phagosomes / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering
  • Sequestosome-1 Protein
  • Serine / immunology
  • Serine / metabolism
  • Tuberculosis / immunology
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Atg7 protein, mouse
  • Heat-Shock Proteins
  • Interleukin-1beta
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Green Fluorescent Proteins
  • Serine
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Rab8b protein, mouse
  • rab GTP-Binding Proteins
  • Autophagy-Related Protein 7