Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro.
Identifieur interne : 000119 ( Ncbi/Merge ); précédent : 000118; suivant : 000120Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro.
Auteurs : H. Beck [Allemagne] ; G. Schwarz ; C J Schröter ; M. Deeg ; D. Baier ; S. Stevanovic ; E. Weber ; C. Driessen ; H. KalbacherSource :
- European journal of immunology [ 0014-2980 ] ; 2001.
Descripteurs français
- KwdFr :
- Antigènes HLA-DR (métabolisme), Cathepsines (métabolisme), Cysteine endopeptidases (métabolisme), Données de séquences moléculaires, Humains, Lactalbumine (métabolisme), Myoglobine (métabolisme), Protéine basique de la myéline (métabolisme), Protéines végétales, Présentation d'antigène, Séquence d'acides aminés.
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Cathepsins, Cysteine Endopeptidases, HLA-DR Antigens, Lactalbumin, Myelin Basic Protein, Myoglobin.
- Amino Acid Sequence, Antigen Presentation, Humans, Molecular Sequence Data, Plant Proteins.
Abstract
The biochemical characterization of antigen degradation is an important basis for a better understanding of both the immune response and autoimmune diseases mediated by MHC class II molecules. In this study we used high-performance liquid chromatography and mass spectrometry to analyze the processing of myelin basic protein (MBP), a potential autoantigen implicated in the pathogenesis of multiple sclerosis. We resolved the kinetics of MBP processing by lysosomal extracts or purified endocytic proteases, identified the major cleavage sites during this process and assigned them to the activity of proteolytic enzymes. Proteolytic processing of MBP is mostly guided along the hydrophobic regions of the protein. It is initiated by two proteolytic steps (after N(92) and S(110)) that are performed by an asparagine-specific endopeptidase (AEP) and by cathepsin (Cat) S, respectively. The resulting processing intermediates are converted into more than 60 different species of 20-40-mers due to the activity of endopeptidases including CatS, D and L. The fragments thus generated are subsequently degraded by C- or N-terminal trimming. Strikingly, the initial cleavages during MBP processing affect two immunodominant regions of the potential autoantigen [MBP(85-99) and MBP(111-129)] in an inverse manner. CatS directly generates the N terminus of the epitope MBP(111-129) in large quantities during the initial phase of processing, which might explain the immunogenicity of this region in spite of its relatively poor binding to HLA-DR4. In contrast, the dominant cleavage by AEP mediates the destruction of MBP(85-99) unless the epitope is protected, e.g. by binding to HLA-DR. Our results thus characterize the proteolytic events during processing of MBP on a molecular level and suggest a biochemical basis for the immunogenicity of the immunodominant epitopes, which could serve as a guideline for future therapeutic strategies.
DOI: 10.1002/1521-4141(200112)31:12<3726::aid-immu3726>3.0.co;2-o
PubMed: 11745393
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Schwarz</name></author><author><name sortKey="Schroter, C J" sort="Schroter, C J" uniqKey="Schroter C" first="C J" last="Schröter">C J Schröter</name></author><author><name sortKey="Deeg, M" sort="Deeg, M" uniqKey="Deeg M" first="M" last="Deeg">M. Deeg</name></author><author><name sortKey="Baier, D" sort="Baier, D" uniqKey="Baier D" first="D" last="Baier">D. Baier</name></author><author><name sortKey="Stevanovic, S" sort="Stevanovic, S" uniqKey="Stevanovic S" first="S" last="Stevanovic">S. Stevanovic</name></author><author><name sortKey="Weber, E" sort="Weber, E" uniqKey="Weber E" first="E" last="Weber">E. Weber</name></author><author><name sortKey="Driessen, C" sort="Driessen, C" uniqKey="Driessen C" first="C" last="Driessen">C. Driessen</name></author><author><name sortKey="Kalbacher, H" sort="Kalbacher, H" uniqKey="Kalbacher H" first="H" last="Kalbacher">H. 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Beck</name><affiliation wicri:level="3"><nlm:affiliation>Medical and Natural Sciences Research Center, University of Tübingen, Tübingen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical and Natural Sciences Research Center, University of Tübingen, Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Schwarz, G" sort="Schwarz, G" uniqKey="Schwarz G" first="G" last="Schwarz">G. Schwarz</name></author><author><name sortKey="Schroter, C J" sort="Schroter, C J" uniqKey="Schroter C" first="C J" last="Schröter">C J Schröter</name></author><author><name sortKey="Deeg, M" sort="Deeg, M" uniqKey="Deeg M" first="M" last="Deeg">M. Deeg</name></author><author><name sortKey="Baier, D" sort="Baier, D" uniqKey="Baier D" first="D" last="Baier">D. Baier</name></author><author><name sortKey="Stevanovic, S" sort="Stevanovic, S" uniqKey="Stevanovic S" first="S" last="Stevanovic">S. Stevanovic</name></author><author><name sortKey="Weber, E" sort="Weber, E" uniqKey="Weber E" first="E" last="Weber">E. Weber</name></author><author><name sortKey="Driessen, C" sort="Driessen, C" uniqKey="Driessen C" first="C" last="Driessen">C. Driessen</name></author><author><name sortKey="Kalbacher, H" sort="Kalbacher, H" uniqKey="Kalbacher H" first="H" last="Kalbacher">H. Kalbacher</name></author></analytic><series><title level="j">European journal of immunology</title><idno type="ISSN">0014-2980</idno><imprint><date when="2001" type="published">2001</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Antigen Presentation</term><term>Cathepsins (metabolism)</term><term>Cysteine Endopeptidases (metabolism)</term><term>HLA-DR Antigens (metabolism)</term><term>Humans</term><term>Lactalbumin (metabolism)</term><term>Molecular Sequence Data</term><term>Myelin Basic Protein (metabolism)</term><term>Myoglobin (metabolism)</term><term>Plant Proteins</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antigènes HLA-DR (métabolisme)</term><term>Cathepsines (métabolisme)</term><term>Cysteine endopeptidases (métabolisme)</term><term>Données de séquences moléculaires</term><term>Humains</term><term>Lactalbumine (métabolisme)</term><term>Myoglobine (métabolisme)</term><term>Protéine basique de la myéline (métabolisme)</term><term>Protéines végétales</term><term>Présentation d'antigène</term><term>Séquence d'acides aminés</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cathepsins</term><term>Cysteine Endopeptidases</term><term>HLA-DR Antigens</term><term>Lactalbumin</term><term>Myelin Basic Protein</term><term>Myoglobin</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes HLA-DR</term><term>Cathepsines</term><term>Cysteine endopeptidases</term><term>Lactalbumine</term><term>Myoglobine</term><term>Protéine basique de la myéline</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Antigen Presentation</term><term>Humans</term><term>Molecular Sequence Data</term><term>Plant Proteins</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Données de séquences moléculaires</term><term>Humains</term><term>Protéines végétales</term><term>Présentation d'antigène</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The biochemical characterization of antigen degradation is an important basis for a better understanding of both the immune response and autoimmune diseases mediated by MHC class II molecules. In this study we used high-performance liquid chromatography and mass spectrometry to analyze the processing of myelin basic protein (MBP), a potential autoantigen implicated in the pathogenesis of multiple sclerosis. We resolved the kinetics of MBP processing by lysosomal extracts or purified endocytic proteases, identified the major cleavage sites during this process and assigned them to the activity of proteolytic enzymes. Proteolytic processing of MBP is mostly guided along the hydrophobic regions of the protein. It is initiated by two proteolytic steps (after N(92) and S(110)) that are performed by an asparagine-specific endopeptidase (AEP) and by cathepsin (Cat) S, respectively. The resulting processing intermediates are converted into more than 60 different species of 20-40-mers due to the activity of endopeptidases including CatS, D and L. The fragments thus generated are subsequently degraded by C- or N-terminal trimming. Strikingly, the initial cleavages during MBP processing affect two immunodominant regions of the potential autoantigen [MBP(85-99) and MBP(111-129)] in an inverse manner. CatS directly generates the N terminus of the epitope MBP(111-129) in large quantities during the initial phase of processing, which might explain the immunogenicity of this region in spite of its relatively poor binding to HLA-DR4. In contrast, the dominant cleavage by AEP mediates the destruction of MBP(85-99) unless the epitope is protected, e.g. by binding to HLA-DR. Our results thus characterize the proteolytic events during processing of MBP on a molecular level and suggest a biochemical basis for the immunogenicity of the immunodominant epitopes, which could serve as a guideline for future therapeutic strategies.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">11745393</PMID><DateCompleted><Year>2002</Year><Month>01</Month><Day>24</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>05</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0014-2980</ISSN><JournalIssue CitedMedium="Print"><Volume>31</Volume><Issue>12</Issue><PubDate><Year>2001</Year><Month>Dec</Month></PubDate></JournalIssue><Title>European journal of immunology</Title><ISOAbbreviation>Eur. J. Immunol.</ISOAbbreviation></Journal><ArticleTitle>Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro.</ArticleTitle><Pagination><MedlinePgn>3726-36</MedlinePgn></Pagination><Abstract><AbstractText>The biochemical characterization of antigen degradation is an important basis for a better understanding of both the immune response and autoimmune diseases mediated by MHC class II molecules. In this study we used high-performance liquid chromatography and mass spectrometry to analyze the processing of myelin basic protein (MBP), a potential autoantigen implicated in the pathogenesis of multiple sclerosis. We resolved the kinetics of MBP processing by lysosomal extracts or purified endocytic proteases, identified the major cleavage sites during this process and assigned them to the activity of proteolytic enzymes. Proteolytic processing of MBP is mostly guided along the hydrophobic regions of the protein. It is initiated by two proteolytic steps (after N(92) and S(110)) that are performed by an asparagine-specific endopeptidase (AEP) and by cathepsin (Cat) S, respectively. The resulting processing intermediates are converted into more than 60 different species of 20-40-mers due to the activity of endopeptidases including CatS, D and L. The fragments thus generated are subsequently degraded by C- or N-terminal trimming. Strikingly, the initial cleavages during MBP processing affect two immunodominant regions of the potential autoantigen [MBP(85-99) and MBP(111-129)] in an inverse manner. CatS directly generates the N terminus of the epitope MBP(111-129) in large quantities during the initial phase of processing, which might explain the immunogenicity of this region in spite of its relatively poor binding to HLA-DR4. In contrast, the dominant cleavage by AEP mediates the destruction of MBP(85-99) unless the epitope is protected, e.g. by binding to HLA-DR. Our results thus characterize the proteolytic events during processing of MBP on a molecular level and suggest a biochemical basis for the immunogenicity of the immunodominant epitopes, which could serve as a guideline for future therapeutic strategies.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Beck</LastName><ForeName>H</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Medical and Natural Sciences Research Center, University of Tübingen, Tübingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schwarz</LastName><ForeName>G</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Schröter</LastName><ForeName>C J</ForeName><Initials>CJ</Initials></Author><Author ValidYN="Y"><LastName>Deeg</LastName><ForeName>M</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Baier</LastName><ForeName>D</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Stevanovic</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Weber</LastName><ForeName>E</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Driessen</LastName><ForeName>C</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Kalbacher</LastName><ForeName>H</ForeName><Initials>H</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Eur J Immunol</MedlineTA><NlmUniqueID>1273201</NlmUniqueID><ISSNLinking>0014-2980</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006684">HLA-DR Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004676">Myelin Basic Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009211">Myoglobin</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010940">Plant Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>9013-90-5</RegistryNumber><NameOfSubstance UI="D007768">Lactalbumin</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.-</RegistryNumber><NameOfSubstance UI="D002403">Cathepsins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="D003546">Cysteine Endopeptidases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.27</RegistryNumber><NameOfSubstance UI="C028217">cathepsin S</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.34</RegistryNumber><NameOfSubstance UI="C069586">asparaginylendopeptidase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000595" MajorTopicYN="N">Amino Acid Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017951" MajorTopicYN="Y">Antigen Presentation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002403" MajorTopicYN="N">Cathepsins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003546" MajorTopicYN="N">Cysteine Endopeptidases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006684" MajorTopicYN="N">HLA-DR Antigens</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007768" MajorTopicYN="N">Lactalbumin</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008969" MajorTopicYN="N">Molecular Sequence Data</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004676" MajorTopicYN="N">Myelin Basic Protein</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009211" MajorTopicYN="N">Myoglobin</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010940" MajorTopicYN="Y">Plant Proteins</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2001</Year><Month>12</Month><Day>18</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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Baier</name><name sortKey="Deeg, M" sort="Deeg, M" uniqKey="Deeg M" first="M" last="Deeg">M. Deeg</name><name sortKey="Driessen, C" sort="Driessen, C" uniqKey="Driessen C" first="C" last="Driessen">C. Driessen</name><name sortKey="Kalbacher, H" sort="Kalbacher, H" uniqKey="Kalbacher H" first="H" last="Kalbacher">H. Kalbacher</name><name sortKey="Schroter, C J" sort="Schroter, C J" uniqKey="Schroter C" first="C J" last="Schröter">C J Schröter</name><name sortKey="Schwarz, G" sort="Schwarz, G" uniqKey="Schwarz G" first="G" last="Schwarz">G. Schwarz</name><name sortKey="Stevanovic, S" sort="Stevanovic, S" uniqKey="Stevanovic S" first="S" last="Stevanovic">S. Stevanovic</name><name sortKey="Weber, E" sort="Weber, E" uniqKey="Weber E" first="E" last="Weber">E. Weber</name></noCountry><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Beck, H" sort="Beck, H" uniqKey="Beck H" first="H" last="Beck">H. 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