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标题：Lysosomal cathepsin D mediates endogenous mucin glycodomain catabolism in mammals
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作者：Kayvon Pedram ; Nouf N. Laqtom ; D. Judy Shon 等
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：39
DOI：10.1073/pnas.2117105119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Mucins are densely O-glycosylated proteins found on the surfaces of many cells in the human body. In order to break down mucin glycodomains, cells must catabolize both the peptide backbone and the appended glycans. In mammals, these two processes were thought to occur largely independently. Here, we show that the human lysosomal enzyme cathepsin D can proteolyze fully glycosylated mucin domains into glycopeptides and that mucins accumulate in some tissues when cathepsin D activity is lost. These findings suggest a mammalian pathway for endogenous mucin glycodomain catabolism, with implications for major histocompatibility complex loading of glycopeptides and tumor extracellular matrix degradation, as well as potential therapies to reverse pathological mucin accumulation. Mucins are functionally implicated in a range of human pathologies, including cystic fibrosis, influenza, bacterial endocarditis, gut dysbiosis, and cancer. These observations have motivated the study of mucin biosynthesis as well as the development of strategies for inhibition of mucin glycosylation. Mammalian pathways for mucin catabolism, however, have remained underexplored. The canonical view, derived from analysis of N-glycoproteins in human lysosomal storage disorders, is that glycan degradation and proteolysis occur sequentially. Here, we challenge this view by providing genetic and biochemical evidence supporting mammalian proteolysis of heavily O-glycosylated mucin domains without prior deglycosylation. Using activity screening coupled with mass spectrometry, we ascribed mucin-degrading activity in murine liver to the lysosomal protease cathepsin D. Glycoproteomics of substrates digested with purified human liver lysosomal cathepsin D provided direct evidence for proteolysis within densely O-glycosylated domains. Finally, knockout of cathepsin D in a murine model of the human lysosomal storage disorder neuronal ceroid lipofuscinosis 10 resulted in accumulation of mucins in liver-resident macrophages. Our findings imply that mucin-degrading activity is a component of endogenous pathways for glycoprotein catabolism in mammalian tissues.
关键词：enO-glycosylationmucincatabolismproteasecathepsin