Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system

TY - JOUR

T1 - Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system

A1 - Goh,Eddy T. H.

A1 - Arthur,J. Simon C.

A1 - Cheung,Peter C. F.

A1 - Akira,Shizuo

A1 - Toth,Rachel

A1 - Cohen,Philip

AU - Goh,Eddy T. H.

AU - Arthur,J. Simon C.

AU - Cheung,Peter C. F.

AU - Akira,Shizuo

AU - Toth,Rachel

AU - Cohen,Philip

PY - 2012/1/1

Y1 - 2012/1/1

N2 - <p>The E3 ubiquitin ligase Pellino 1 can be interconverted between inactive and active forms by a reversible phosphorylation mechanism. In vitro, phosphorylation and activation can be catalysed by either the IRAKs [IL (interleukin)-1-receptor-associated kinases] IRAK1 and IRAK4, or the IKK {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase}-related kinases [IKK epsilon and TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-kappa B activator}-binding kinase 1)]. In the present study we establish that IRAK I is the major protein kinase that mediates the IL-1-stimulated activation of Pellino 1 in MEFs (mouse embryonic fibroblasts) or HEK (human embryonic kidney)-293 cells, whereas the IKK-related kinases activate Pellino 1 in TNF alpha-stimulated MEFs. The IKK-related kinases are also the major protein kinases that activate Pellino 1 in response to TLR (Toll-like receptor) ligands that signal via the adaptors MyD88 (myeloid differentiation primary response gene 88) and/or TRIF [TIR (Toll/IL-1 receptor) domain-containing adaptor protein inducing interferon beta]. The present studies demonstrate that, surprisingly, the ligands that signal via MyD88 do not always employ the same protein kinase to activate Pellino 1. Our results also establish that neither the catalytic activity of IRAK1 nor the activation of Pellino 1 is required for the initial transient activation of NF-kappa B and MAPKs (mitogen-activated protein kinases) that is triggered by IL-1 or TNF alpha in MEFs, or by TLR ligands in macrophages. The activation of Pellino 1 provides the first direct readout for IRAK1 catalytic activity in cells.</p>

AB - <p>The E3 ubiquitin ligase Pellino 1 can be interconverted between inactive and active forms by a reversible phosphorylation mechanism. In vitro, phosphorylation and activation can be catalysed by either the IRAKs [IL (interleukin)-1-receptor-associated kinases] IRAK1 and IRAK4, or the IKK {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase}-related kinases [IKK epsilon and TBK1 (TANK {TRAF [TNF (tumour-necrosis-factor)-receptor-associated factor]-associated NF-kappa B activator}-binding kinase 1)]. In the present study we establish that IRAK I is the major protein kinase that mediates the IL-1-stimulated activation of Pellino 1 in MEFs (mouse embryonic fibroblasts) or HEK (human embryonic kidney)-293 cells, whereas the IKK-related kinases activate Pellino 1 in TNF alpha-stimulated MEFs. The IKK-related kinases are also the major protein kinases that activate Pellino 1 in response to TLR (Toll-like receptor) ligands that signal via the adaptors MyD88 (myeloid differentiation primary response gene 88) and/or TRIF [TIR (Toll/IL-1 receptor) domain-containing adaptor protein inducing interferon beta]. The present studies demonstrate that, surprisingly, the ligands that signal via MyD88 do not always employ the same protein kinase to activate Pellino 1. Our results also establish that neither the catalytic activity of IRAK1 nor the activation of Pellino 1 is required for the initial transient activation of NF-kappa B and MAPKs (mitogen-activated protein kinases) that is triggered by IL-1 or TNF alpha in MEFs, or by TLR ligands in macrophages. The activation of Pellino 1 provides the first direct readout for IRAK1 catalytic activity in cells.</p>

KW - interleukin-1-receptor-associated kinase (IRAK)

KW - inhibitor of nuclear factor kappa B kinase (IKK)

KW - TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor kappa B activator]-binding kinase 1 (TBK1)

KW - tumour necrosis factor alpha (TNF alpha)

KW - Toll-like receptor (TLR)

KW - FHA DOMAIN

KW - IRAK1

KW - POLYUBIQUITINATION

KW - PHOSPHORYLATION

KW - BINDING

KW - FAMILY

KW - ROLES

KW - TAK1

U2 - 10.1042/BJ20111415

DO - 10.1042/BJ20111415

M1 - Article

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

VL - 441

SP - 339

EP - 346

ER -