ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses.
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.
Papoutsopoulou
Stamatia
S
Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, UK.
Symons
Antony
A
Tharmalingham
Tharsana
T
Belich
Monica P
MP
Kaiser
Frank
F
Kioussis
Dimitris
D
O'Garra
Anne
A
Tybulewicz
Victor
V
Ley
Steven C
SC
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C503281:Tnip2 protein, mouse; D051197:Toll-Like Receptor 4; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse