Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling

• Published in: Science signaling 2013-07, Vol.6 (286), p.ra64-ra64
• Main Authors: Ersoy, Baran A, Tarun, Akansha, D'Aquino, Katharine, Hancer, Nancy J, Ukomadu, Chinweike, White, Morris F, Michel, Thomas, Manning, Brendan D, Cohen, David E
• Format: Article
• Language: English
• Subjects: Animals; Glucose - metabolism; HEK293 Cells; Homeostasis; Humans; Inhibitory Concentration 50; Insulin - metabolism; Liver - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes - metabolism; Phospholipid Transfer Proteins - metabolism; Phosphorylation; Signal Transduction; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.2004111

Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP-THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor.