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A new flavor of cellular Atg8-family protein lipidation - alternative conjugation to phosphatidylserine during CASM.
Durgan J, Florey O
Atg8-family protein lipidation is the most commonly used marker for monitoring autophagy. During macroautophagy, Atg8-family proteins are specifically conjugated to phosphatidylethanolamine (PE) in forming, double-membrane autophagosomes. A distinct, non-canonical autophagy pathway also operates, characterized by the Conjugation of ATG8s to endolysosomal Single Membranes (CASM). In our new study, we show that CASM is associated with the alternative conjugation of Atg8-family proteins to phosphatidylserine (PS), and PE, in response to various cellular stimuli. We also discover differences in the regulation of conjugation to PE and PS by ATG4s, and altered dynamics between the two species. The identification of alternative Atg8-family protein PS lipidation opens up exciting new questions on the roles, regulation and biology of Atg8-family proteins during non-canonical autophagy.
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Autophagy,
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12 Jul 2021
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Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine.
Durgan J, Lystad AH, Sloan K, Carlsson SR, Wilson MI, Marcassa E, Ulferts R, Webster J, Lopez-Clavijo AF, Wakelam MJ, Beale R, Simonsen A, Oxley D, Florey O
Autophagy is a fundamental catabolic process that uses a unique post-translational modification, the conjugation of ATG8 protein to phosphatidylethanolamine (PE). ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway involving conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments, with key functions in immunity, vision, and neurobiology. It is widely assumed that CASM involves the same conjugation of ATG8 to PE, but this has not been formally tested. Here, we discover that all ATG8s can also undergo alternative lipidation to phosphatidylserine (PS) during CASM, induced pharmacologically, by LC3-associated phagocytosis or influenza A virus infection, in mammalian cells. Importantly, ATG8-PS and ATG8-PE adducts are differentially delipidated by the ATG4 family and bear different cellular dynamics, indicating significant molecular distinctions. These results provide important insights into autophagy signaling, revealing an alternative form of the hallmark ATG8 lipidation event. Furthermore, ATG8-PS provides a specific "molecular signature" for the non-canonical autophagy pathway.
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Molecular cell,
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16 Apr 2021
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CDK1, the Other 'Master Regulator' of Autophagy.
Odle RI, Florey O, Ktistakis NT, Cook SJ
Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient availability. However, the regulation of these processes, and mTORC1 itself, is different during mitosis, and this has remained an area of significant controversy; for example, studies have argued that autophagy is either repressed or highly active during mitosis. Recent studies have shown that autophagy initiation is repressed, and cap-dependent mRNA translation is maintained during mitosis despite mTORC1 activity being repressed. This is achieved in large part by a switch from mTORC1- to cyclin-dependent kinase 1 (CDK1)-mediated regulation. Here, we review the history and recent advances and seek to present a unifying model to inform the future study of autophagy and mTORC1 during mitosis.
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Trends in cell biology,
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30 Nov 2020
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