Receptor‐mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy |
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| Authors: | Amelia E Ohnstad Jose M Delgado Brian J North Isha Nasa Arminja N Kettenbach Sebastian W Schultz Christopher J Shoemaker |
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| Affiliation: | 1. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover NH, USA ; 2. Norris Cotton Cancer Center, Lebanon NH, USA ; 3. Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo Norway ; 4. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo Norway |
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| Abstract: | Autophagosome formation requires multiple autophagy‐related (ATG) factors. However, we find that a subset of autophagy substrates remains robustly targeted to the lysosome in the absence of several core ATGs, including the LC3 lipidation machinery. To address this unexpected result, we performed genome‐wide CRISPR screens identifying genes required for NBR1 flux in ATG7KO cells. We find that ATG7‐independent autophagy still requires canonical ATG factors including FIP200. However, in the absence of LC3 lipidation, additional factors are required including TAX1BP1 and TBK1. TAX1BP1''s ability to cluster FIP200 around NBR1 cargo and induce local autophagosome formation enforces cargo specificity and replaces the requirement for lipidated LC3. In support of this model, we define a ubiquitin‐independent mode of TAX1BP1 recruitment to NBR1 puncta, highlighting that TAX1BP1 recruitment and clustering, rather than ubiquitin binding per se, is critical for function. Collectively, our data provide a mechanistic basis for reports of selective autophagy in cells lacking the lipidation machinery, wherein receptor‐mediated clustering of upstream autophagy factors drives continued autophagosome formation. |
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| Keywords: | ATG7 autophagosome NBR1 selective autophagy TAX1BP1 |
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