Glycan degradation promotes macroautophagy

Baudot, A. D. et al. (2022) Glycan degradation promotes macroautophagy. Proceedings of the National Academy of Sciences of the United States of America, 119(26), e211150611. (doi: 10.1073/pnas.2111506119) (PMID:35737835)

Abstract

Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521–527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-L-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis—a disease characterized by inactivating mutations in FUCA1 [Stepien et al., Genes (Basel) 11, E1383 (2020)]—glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome–lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.

• Item Type: Articles
• Additional Information: This work was funded by Worldwide Cancer Research (Grant 16-1194), Cancer Research UK (Grant A17196; core funding to the Cancer Research UK Beatson Institute and Grant A22903; core funding to the K.M.R. laboratory and Grant A29800; core funding to the S.Z. laboratory), and Sir Henry Wellcome Postdoctoral Fellowship 221607/Z/20/Z (to V.M.-Y.W.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leach, Dr Joshua and Marchesi, Dr Francesco and Nixon, Mr Colin and Lilla, Dr Sergio and Long, Dr Jaclyn and Baudot, Dr Alice and Zanivan, Professor Sara and Ghaffar, Miss Farah and Paulus-Hock, Mrs Viola and Strathdee, Mr Douglas and Ryan, Dr Kevin
• Authors: Baudot, A. D., Wang, V. M.-Y., Leach, J. D., O’Prey, J., Long, J. S., Paulus-Hock, V., Lilla, S., Thomson, D. M., Greenhorn, J., Ghaffar, F., Nixon, C., Helfrich, M. H., Strathdee, D., Pratt, J., Marchesi, F., Zanivan, S., and Ryan, K. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 22 June 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Proceedings of the National Academy of Sciences of the United States of America 119(26): e211150611
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.5525/gla.researchdata.1280