Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter

Danielle L. Schmitt, Stephanie D. Curtis, Anne C. Lyons, Jin-fan Zhang, Mingyuan Chen, Catherine Y. He, Sohum Mehta, Reuben J. Shaw and Jin Zhang ()
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Danielle L. Schmitt: University of California San Diego
Stephanie D. Curtis: The Salk Institute for Biological Studies
Anne C. Lyons: University of California San Diego
Jin-fan Zhang: University of California San Diego
Mingyuan Chen: University of California San Diego
Catherine Y. He: University of California San Diego
Sohum Mehta: University of California San Diego
Reuben J. Shaw: The Salk Institute for Biological Studies
Jin Zhang: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics which coordinates metabolism by phosphorylating a plethora of substrates throughout the cell. But how AMPK activity is regulated at different subcellular locations for precise spatiotemporal control over metabolism is unclear. Here we present a sensitive, single-fluorophore AMPK activity reporter (ExRai AMPKAR), which reveals distinct kinetic profiles of AMPK activity at the mitochondria, lysosome, and cytoplasm. Genetic deletion of the canonical upstream kinase liver kinase B1 (LKB1) results in slower AMPK activity at lysosomes but does not affect the response amplitude at lysosomes or mitochondria, in sharp contrast to the necessity of LKB1 for maximal cytoplasmic AMPK activity. We further identify a mechanism for AMPK activity in the nucleus, which results from cytoplasmic to nuclear shuttling of AMPK. Thus, ExRai AMPKAR enables illumination of the complex subcellular regulation of AMPK signaling.

Date: 2022
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DOI: 10.1038/s41467-022-31190-x

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