title: Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling.
abstract: 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.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Baran A
authors.initials: BA
authors.lastname: Ersoy
authors.forename: Akansha
authors.initials: A
authors.lastname: Tarun
authors.forename: Katharine
authors.initials: K
authors.lastname: D'Aquino
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Hancer
authors.forename: Chinweike
authors.initials: C
authors.lastname: Ukomadu
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Thomas
authors.initials: T
authors.lastname: Michel
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; D049294:Phospholipid Transfer Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C514740:ACOT13 protein, human; C544602:Acot13 protein, mouse; D013869:Thiolester Hydrolases; D005947:Glucose
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