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However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in\u00a0vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrP\n                    <jats:sup>C<\/jats:sup>\n                    \u03b2-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrP\n                    <jats:sup>C<\/jats:sup>\n                    \u2019s N-terminal domain. For wild-type mouse and human PrP\n                    <jats:sup>C<\/jats:sup>\n                    substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP &gt; mouse DPP4 &gt; human DPP4 and human FAP &gt; mouse FAP &gt; mouse DPP4 &gt;&gt; human DPP4, respectively. C2 levels relative to total PrP\n                    <jats:sup>C<\/jats:sup>\n                    were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4\/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2\n                    <jats:sup>Sc<\/jats:sup>\n                    and total PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors\/modulators affect the physiology and pathogenic potential of PrP\n                    <jats:sup>C<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2209815120","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T16:15:16Z","timestamp":1672157716000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2590-9555","authenticated-orcid":false,"given":"Andrew R.","family":"Castle","sequence":"first","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6875-113X","authenticated-orcid":false,"given":"Sang-Gyun","family":"Kang","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0447-7722","authenticated-orcid":false,"given":"Ghazaleh","family":"Eskandari-Sedighi","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serene","family":"Wohlgemuth","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"My-Anh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada"},{"name":"Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-8127","authenticated-orcid":false,"given":"Daniel J.","family":"Drucker","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3981-0241","authenticated-orcid":false,"given":"Erin E.","family":"Mulvihill","sequence":"additional","affiliation":[{"name":"University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada"},{"name":"Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-4616","authenticated-orcid":false,"given":"David","family":"Westaway","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada"},{"name":"Department of Biochemistry, 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