α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro

Lifu Wang and David L. Brautigan ()
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Lifu Wang: Immunology and Cancer Biology, Center for Cell Signaling, University of Virginia School of Medicine
David L. Brautigan: Immunology and Cancer Biology, Center for Cell Signaling, University of Virginia School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2565

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