ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism

ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism

ABSTRACT Macroautophagy/autophagy is an essential catabolic process that targets a wide variety of cellular components including proteins, organelles, and pathogens. ATG7, a protein involved in the autophagy process, plays a crucial role in maintaining cellular homeostasis and can contribute to the...

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Bibliographic Details
Published in:Traffic (Copenhagen, Denmark) Vol. 25; no. 4; pp. e12933 - n/a
Main Authors: Ostacolo, Kevin, López García de Lomana, Adrián, Larat, Clémence, Hjaltalin, Valgerdur, Holm, Kristrun Yr, Hlynsdóttir, Sigríður S., Soucheray, Margaret, Sooman, Linda, Rolfsson, Ottar, Krogan, Nevan J., Steingrimsson, Eirikur, Swaney, Danielle L., Ogmundsdottir, Margret H.
Format: Journal Article
Language:English
Published: Former Munksgaard John Wiley & Sons A/S 01-04-2024
Wiley Subscription Services, Inc
Subjects:
ATG7
Autophagosomes - metabolism
Autophagy
Autophagy-Related Proteins - metabolism
Energy Metabolism
glycolysis
GTEx
Homeostasis
Humans
isoforms
lipidation
Mass spectroscopy
Metabolism
Microtubule-Associated Proteins - metabolism
mitochondrial activity
Organelles
PPI
Protein interaction
Protein Isoforms - metabolism
Protein purification
Proteins
GTEx
autophagy
lipidation
glycolysis
PPI
isoforms
ATG7
mitochondrial activity
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Summary:ABSTRACT Macroautophagy/autophagy is an essential catabolic process that targets a wide variety of cellular components including proteins, organelles, and pathogens. ATG7, a protein involved in the autophagy process, plays a crucial role in maintaining cellular homeostasis and can contribute to the development of diseases such as cancer. ATG7 initiates autophagy by facilitating the lipidation of the ATG8 proteins in the growing autophagosome membrane. The noncanonical isoform ATG7(2) is unable to perform ATG8 lipidation; however, its cellular regulation and function are unknown. Here, we uncovered a distinct regulation and function of ATG7(2) in contrast with ATG7(1), the canonical isoform. First, affinity‐purification mass spectrometry analysis revealed that ATG7(2) establishes direct protein–protein interactions (PPIs) with metabolic proteins, whereas ATG7(1) primarily interacts with autophagy machinery proteins. Furthermore, we identified that ATG7(2) mediates a decrease in metabolic activity, highlighting a novel splice‐dependent function of this important autophagy protein. Then, we found a divergent expression pattern of ATG7(1) and ATG7(2) across human tissues. Conclusively, our work uncovers the divergent patterns of expression, protein interactions, and function of ATG7(2) in contrast to ATG7(1). These findings suggest a molecular switch between main catabolic processes through isoform‐dependent expression of a key autophagy gene. Here, we characterized the protein interactome, function, and expression pattern of a noncanonical isoform of ATG7, ATG7(2). Using different cell models, we revealed through affinity‐purification mass spectrometry analysis, that ATG7(2) lacks the interaction with autophagy machinery proteins. Interestingly, ATG7(2) binds metabolic proteins. Furthermore, we identified that ATG7(2) mediates a decrease in metabolic activity. Then, we identified a divergent pattern of expression of the canonical isoform, ATG7(1), and ATG7(2) across human tissues, highlighting different regulation of the two isoforms.
Bibliography:Funding
This work was supported by Icelandic Research Fund grants (Grants 184727‐051, 228586‐051, and 207307‐051), Icelandic Cancer Society Research Fund grant and National Institutes of Health funding U54 CA209891.
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ISSN:1398-9219
1600-0854
1600-0854
DOI:10.1111/tra.12933