The Regulation of Basal Autophagic Flux by an ATG13-ATG101 Complex.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology(2022)
摘要
Autophagy is an essential cellular process by which cellular debris is collected and broken down in the lysosome. Cancer cells rely on autophagy for survival during chemotherapy treatment and periods of hypoxia within solid tumors. In this project, we investigate the ATG13-ATG101 protein complex, a sub-complex of the ULK1 initiatory complex whose regulatory role in autophagy is not completely understood. Our recent data demonstrate that an ULK1-independent ATG13-ATG101 complex is essential for the basal autophagic degradation of protein aggregates-a process known as aggrephagy. Furthermore, we found that the ULK1-independent ATG13-ATG101 complex traffics to condensates of poly-ubiquitinated protein aggregates where it colocalizes with the autophagy regulator ATG9A. Our current data suggest that this ATG13-ATG101 complex cooperates with ATG9A in the degradation of these protein aggregates. To further elucidate the function of the ATG13-ATG101 complex, we have developed a protein-fragment complementation assay using a novel split TurboID (BioID) system in which complementary halves of TurboID are fused to ATG13 and ATG101. Using this split BioID system, together with quantitative LC-MS/MS and mutants of ATG13 that cannot bind ULK1, we are identifying interactors that are unique to the ULK1-independent ATG13-ATG101 complex. Based on previous data, we hypothesize that the ATG13-ATG101 sub-complex participates in ATG9A trafficking pathways and recruitment of autophagy regulators to protein aggregate condensates. Thus, our project characterizes the first proximity interactome for the ATG13-ATG101 complex. 1. Kannangara, A. R.; Poole, D. M.; McEwan, C. M.; Youngs, J. C.; Weerasekara, V. K.; Thornock, A. M.; Lazaro, M. T.; Balasooriya, E. R.; Oh, L. M.; Soderblom, E. J.; Lee, J. J.; Simmons, D. L.; Andersen, J. L., BioID reveals an ATG9A interaction with ATG13-ATG101 in the degradation of p62/SQSTM1-ubiquitin clusters. EMBO Rep2021, e51136.
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关键词
basal autophagic flux
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