期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：26
DOI：10.1073/pnas.2111506119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Macroautophagy preserves cellular integrity and, as a result, protects against various forms of human disease. It is therefore imperative that we understand how the process is controlled. Our finding that appropriate glycan degradation is an important and distinct control point for successful macroautophagy represents a fundamental insight into this process. Furthermore, our finding that fucosidosis, a congenital disorder of glycosylation, involves impairment of macroautophagy opens up new possibilities for treating this currently incurable disease.
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.
