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

Stamatia Papoutsopoulou; Antony Symons; Tharsana Tharmalingham; Monica P. Belich; Frank Kaiser; Dimitris Kioussis; Anne O'Garra; Victor Tybulewicz; Steven C. Ley

doi:10.1038/ni1334

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

Stamatia Papoutsopoulou, Antony Symons, Tharsana Tharmalingham, Monica P. Belich, Frank Kaiser, Dimitris Kioussis, Anne O'Garra, Victor Tybulewicz, Steven C. Ley^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Humangenetik

National Institute of Medical Research

75 Zitate (Scopus)

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-κB 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-κB. 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 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

Originalsprache	Englisch
Zeitschrift	Nature Immunology
Jahrgang	7
Ausgabenummer	6
Seiten (von - bis)	606-615
Seitenumfang	10
ISSN	1529-2908
DOIs	https://doi.org/10.1038/ni1334
Publikationsstatus	Veröffentlicht - 06.2006

Fördermittel

We thank T. Kitamura and P. Tsichlis for reagents; S. Beinke and B. Seddon (Division of Immune Cell Biology, NIMR) for critical reading of the manuscript; A. Garefalaki and U. Menzel (Division of Molecular Immunology, NIMR) for help with culturing targeted embryonic stem cells; M. Holman (Division of Immunoregulation, NIMR) for advice on LPS injections; and the NIMR Photographics department, NIMR Biological Services and other members of the Ley laboratory for help during the course of this work. Supported by the UK Medical Research Council and Arthritis Research Campaign (L0549 to A.S. and 16053 to F.K.).

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Querschnittsbereich: Medizinische Genetik

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

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-κB 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-κB. 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 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.",

author = "Stamatia Papoutsopoulou and Antony Symons and Tharsana Tharmalingham and Belich, \{Monica P.\} and Frank Kaiser and Dimitris Kioussis and Anne O'Garra and Victor Tybulewicz and Ley, \{Steven C.\}",

note = "Funding Information: We thank T. Kitamura and P. Tsichlis for reagents; S. Beinke and B. Seddon (Division of Immune Cell Biology, NIMR) for critical reading of the manuscript; A. Garefalaki and U. Menzel (Division of Molecular Immunology, NIMR) for help with culturing targeted embryonic stem cells; M. Holman (Division of Immunoregulation, NIMR) for advice on LPS injections; and the NIMR Photographics department, NIMR Biological Services and other members of the Ley laboratory for help during the course of this work. Supported by the UK Medical Research Council and Arthritis Research Campaign (L0549 to A.S. and 16053 to F.K.).",

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doi = "10.1038/ni1334",

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journal = "Nature Immunology",

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T1 - ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses

AU - Papoutsopoulou, Stamatia

AU - Symons, Antony

AU - Tharmalingham, Tharsana

AU - Belich, Monica P.

AU - Kaiser, Frank

AU - Kioussis, Dimitris

AU - O'Garra, Anne

AU - Tybulewicz, Victor

AU - Ley, Steven C.

N1 - Funding Information: We thank T. Kitamura and P. Tsichlis for reagents; S. Beinke and B. Seddon (Division of Immune Cell Biology, NIMR) for critical reading of the manuscript; A. Garefalaki and U. Menzel (Division of Molecular Immunology, NIMR) for help with culturing targeted embryonic stem cells; M. Holman (Division of Immunoregulation, NIMR) for advice on LPS injections; and the NIMR Photographics department, NIMR Biological Services and other members of the Ley laboratory for help during the course of this work. Supported by the UK Medical Research Council and Arthritis Research Campaign (L0549 to A.S. and 16053 to F.K.).

PY - 2006/6

Y1 - 2006/6

N2 - 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-κB 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-κB. 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 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

AB - 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-κB 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-κB. 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 1β. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

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ER -

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

Abstract

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