ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses

Nat Immunol. 2006 Jun;7(6):606-15. doi: 10.1038/ni1334. Epub 2006 Apr 23.

Abstract

The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-kappaB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-kappaB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1beta. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • B-Lymphocytes / immunology
  • CD40 Antigens / metabolism
  • Early Growth Response Protein 1 / metabolism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Immunity, Innate*
  • Interleukin-1 / metabolism
  • Lipopolysaccharides / immunology
  • MAP Kinase Kinase Kinases / metabolism*
  • Macrophages / immunology
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CD40 Antigens
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Interleukin-1
  • Lipopolysaccharides
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnip2 protein, mouse
  • Toll-Like Receptor 4
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse