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Regulation of the autophagy protein LC3 by phosphorylation

Salvatore J. Cherra III, Scott M. Kulich, Guy Uechi, Manimalha Balasubramani, John Mountzouris, Billy W. Day and Charleen T. Chu
The Journal of Cell Biology
Vol. 190, No. 4 (AUGUST 23, 2010), pp. 533-539
Stable URL: http://www.jstor.org/stable/20753844
Page Count: 7
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Regulation of the autophagy protein LC3 by phosphorylation
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Abstract

Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis, and neurodegeneration. Although bulk degradation sustains carbon sources during starvation, autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-related genes has spurred rapid advances in understanding the recruitment of microtubule-associated protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological (MPP⁺) inducers of autophagy caused dephosphorylation of endogenous LC3. The pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent neurite shortening induced by expression of a Parkinson disease—associated G2019S mutation in leucine-rich repeat kinase 2 was inhibited by dibutyryl—cyclic adenosine monophosphate, cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data demonstrate a role for phosphorylation in regulating LC3 activity.

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