Myosin motor Myo1c and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1.
Tumor necrosis factor-alpha (TNF-alpha) signaling through the IkappaB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor kappaB essential modulator (NEMO)/IKK-gamma subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO-IRS-1 interaction, which is essential for TNF-alpha- induced phosphorylation of Ser307-IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-alpha-induced Ser307-IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-beta-binding domain or silencing NEMO blocked the TNF-alpha signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK-IRS-1 complex and function in TNF-alpha-induced insulin resistance.
Nakamori
Yoshitaka
Y
Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
Emoto
Masahiro
M
Fukuda
Naofumi
N
Taguchi
Akihiko
A
Okuya
Shigeru
S
Tajiri
Michiko
M
Miyagishi
Makoto
M
Taira
Kazunari
K
Wada
Yoshinao
Y
Tanizawa
Yukio
Y
D041721:3T3-L1 Cells; D000818:Animals; D005947:Glucose / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D020409:Molecular Motor Proteins; D024461:Myosin Type I; D009218:Myosins / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D012694:Serine / Q000096:biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020409:Molecular Motor Proteins; C470422:Myo1c protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D051550:I-kappa B Kinase; D024461:Myosin Type I; D009218:Myosins; D005947:Glucose