{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:21:10Z","timestamp":1784852470491,"version":"3.55.0"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,27]]},"abstract":"<jats:p>\n                    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                    <jats:italic>N<\/jats:italic>\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\n                    <jats:italic>O<\/jats:italic>\n                    -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\n                    <jats:italic>O<\/jats:italic>\n                    -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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2117105119","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T15:16:45Z","timestamp":1663600605000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Lysosomal cathepsin D mediates endogenous mucin glycodomain catabolism in mammals"],"prefix":"10.1073","volume":"119","author":[{"given":"Kayvon","family":"Pedram","sequence":"first","affiliation":[{"name":"Department of Chemistry, Stanford University, Stanford, CA 94305"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouf N.","family":"Laqtom","sequence":"additional","affiliation":[{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"},{"name":"Department of Chemical Engineering, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-6195","authenticated-orcid":false,"given":"D. Judy","family":"Shon","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stanford University, Stanford, CA 94305"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-4440","authenticated-orcid":false,"given":"Alessandro","family":"Di Spiezio","sequence":"additional","affiliation":[{"name":"Biochemisches Institut, Christian-Albrechts-Universit\u00e4t Kiel, Kiel, Germany D-24098"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-2966","authenticated-orcid":false,"given":"Nicholas M.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stanford University, Stanford, CA 94305"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Saftig","sequence":"additional","affiliation":[{"name":"Biochemisches Institut, Christian-Albrechts-Universit\u00e4t Kiel, Kiel, Germany D-24098"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monther","family":"Abu-Remaileh","sequence":"additional","affiliation":[{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"},{"name":"Department of Chemical Engineering, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4482-2754","authenticated-orcid":false,"given":"Carolyn R.","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stanford University, Stanford, CA 94305"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA 94305"},{"name":"HHMI, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","unstructured":"C. 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Deposited 28 July 2021."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2117105119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T10:27:03Z","timestamp":1676456823000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2117105119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,19]]},"references-count":51,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2022,9,27]]}},"alternative-id":["10.1073\/pnas.2117105119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2117105119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,19]]},"assertion":[{"value":"2021-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2117105119"}}