title: α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro.
abstract: The AMP-activated protein kinase (AMPK) regulates metabolism in normal and pathological conditions and responds to nutrients, hormones, anti-diabetic drugs and physical exercise. AMPK is activated by the kinase LKB1 and inactivated by phosphatases whose identities remain uncertain. Here we show that AMPK associates with α-SNAP, an adapter that enables disassembly of cis-SNARE complexes formed during membrane fusion. Knockdown of α-SNAP activates AMPK to phosphorylate its endogenous substrates acetyl CoA carboxylase and Raptor, and provokes mitochondrial biogenesis. AMPK phosphorylation is rescued from α-SNAP RNA interference by LKB1 knockdown or expression of wild-type but not mutated α-SNAP. Recombinant wild-type but not mutated α-SNAP dephosphorylates pThr172 in AMPKα in vitro. Overexpression of wild-type but not mutated α-SNAP prevents AMPK activation in cells treated with agents to elevate AMP concentration. The mouse α-SNAP mutant hyh (hydrocephalus with hop gait) shows enhanced binding and inhibition of AMPK. By negatively controlling AMPK, α-SNAP therefore potentially coordinates membrane trafficking and metabolism.
authors: Department of Microbiology, Immunology and Cancer Biology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Lifu
authors: L
authors: Wang
authors: David L
authors: DL
authors: Brautigan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D063269:Mitochondrial Turnover / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D034741:RNA, Small Interfering; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D013912:Threonine; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases