Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions
Many questions surround the underlying mechanism for the differential metabolic processing observed for the prion protein (PrP) in healthy and prion-infected mammals. Foremost, the physiological α-cleavage of PrP interrupts a region critical for both toxicity and conversion of cellular PrP (PrPC) in...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.990136/full |
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| author | Charles E. Mays Trang H. T. Trinh Trang H. T. Trinh Glenn Telling Glenn Telling Glenn Telling Hae-Eun Kang Hae-Eun Kang Hae-Eun Kang Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou |
| author_facet | Charles E. Mays Trang H. T. Trinh Trang H. T. Trinh Glenn Telling Glenn Telling Glenn Telling Hae-Eun Kang Hae-Eun Kang Hae-Eun Kang Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou |
| author_sort | Charles E. Mays |
| collection | DOAJ |
| description | Many questions surround the underlying mechanism for the differential metabolic processing observed for the prion protein (PrP) in healthy and prion-infected mammals. Foremost, the physiological α-cleavage of PrP interrupts a region critical for both toxicity and conversion of cellular PrP (PrPC) into its misfolded pathogenic isoform (PrPSc) by generating a glycosylphosphatidylinositol (GPI)-anchored C1 fragment. During prion diseases, alternative β-cleavage of PrP becomes prominent, producing a GPI-anchored C2 fragment with this particular region intact. It remains unexplored whether physical up-regulation of α-cleavage can inhibit disease progression. Furthermore, several pieces of evidence indicate that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 play a much smaller role in the α-cleavage of PrPC than originally believed, thus presenting the need to identify the primary protease(s) responsible. For this purpose, we characterized the ability of plasmin to perform PrP α-cleavage. Then, we conducted functional assays using protein misfolding cyclic amplification (PMCA) and prion-infected cell lines to clarify the role of plasmin-mediated α-cleavage during prion propagation. Here, we demonstrated an inhibitory role of plasmin for PrPSc formation through PrP α-cleavage that increased C1 fragments resulting in reduced prion conversion compared with non-treated PMCA and cell cultures. The reduction of prion infectious titer in the bioassay of plasmin-treated PMCA material also supported the inhibitory role of plasmin on PrPSc replication. Our results suggest that plasmin-mediated endoproteolytic cleavage of PrP may be an important event to prevent prion propagation. |
| first_indexed | 2024-04-11T13:36:42Z |
| format | Article |
| id | doaj.art-aaf27419584e4415ad144a1b62b61338 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-11T13:36:42Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-aaf27419584e4415ad144a1b62b613382022-12-22T04:21:26ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-09-011510.3389/fnmol.2022.990136990136Endoproteolysis of cellular prion protein by plasmin hinders propagation of prionsCharles E. Mays0Trang H. T. Trinh1Trang H. T. Trinh2Glenn Telling3Glenn Telling4Glenn Telling5Hae-Eun Kang6Hae-Eun Kang7Hae-Eun Kang8Chongsuk Ryou9Chongsuk Ryou10Chongsuk Ryou11Chongsuk Ryou12Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, United StatesDepartment of Pharmacy, College of Pharmacy, Hanyang University, Ansan, South KoreaInstitute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South KoreaDepartment of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, United StatesSanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, United StatesDepartment of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United StatesSanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, United StatesDepartment of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United StatesReference Laboratory for Chronic Wasting Disease (CWD), Foreign Animal Disease Division, Animal and Plant Quarantine Agency, Gimcheon, South KoreaDepartment of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, United StatesDepartment of Pharmacy, College of Pharmacy, Hanyang University, Ansan, South KoreaInstitute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South KoreaSanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, United StatesMany questions surround the underlying mechanism for the differential metabolic processing observed for the prion protein (PrP) in healthy and prion-infected mammals. Foremost, the physiological α-cleavage of PrP interrupts a region critical for both toxicity and conversion of cellular PrP (PrPC) into its misfolded pathogenic isoform (PrPSc) by generating a glycosylphosphatidylinositol (GPI)-anchored C1 fragment. During prion diseases, alternative β-cleavage of PrP becomes prominent, producing a GPI-anchored C2 fragment with this particular region intact. It remains unexplored whether physical up-regulation of α-cleavage can inhibit disease progression. Furthermore, several pieces of evidence indicate that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 play a much smaller role in the α-cleavage of PrPC than originally believed, thus presenting the need to identify the primary protease(s) responsible. For this purpose, we characterized the ability of plasmin to perform PrP α-cleavage. Then, we conducted functional assays using protein misfolding cyclic amplification (PMCA) and prion-infected cell lines to clarify the role of plasmin-mediated α-cleavage during prion propagation. Here, we demonstrated an inhibitory role of plasmin for PrPSc formation through PrP α-cleavage that increased C1 fragments resulting in reduced prion conversion compared with non-treated PMCA and cell cultures. The reduction of prion infectious titer in the bioassay of plasmin-treated PMCA material also supported the inhibitory role of plasmin on PrPSc replication. Our results suggest that plasmin-mediated endoproteolytic cleavage of PrP may be an important event to prevent prion propagation.https://www.frontiersin.org/articles/10.3389/fnmol.2022.990136/fullplasminprionendoproteolysisα-cleavagePrPSc propagation |
| spellingShingle | Charles E. Mays Trang H. T. Trinh Trang H. T. Trinh Glenn Telling Glenn Telling Glenn Telling Hae-Eun Kang Hae-Eun Kang Hae-Eun Kang Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou Chongsuk Ryou Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions Frontiers in Molecular Neuroscience plasmin prion endoproteolysis α-cleavage PrPSc propagation |
| title | Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| title_full | Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| title_fullStr | Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| title_full_unstemmed | Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| title_short | Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| title_sort | endoproteolysis of cellular prion protein by plasmin hinders propagation of prions |
| topic | plasmin prion endoproteolysis α-cleavage PrPSc propagation |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.990136/full |
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