hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis
Summary: Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720306203 |
| _version_ | 1818476623045853184 |
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| author | Audrey Xavier Munir A. Al-Zeer Thomas F. Meyer Oliver Daumke |
| author_facet | Audrey Xavier Munir A. Al-Zeer Thomas F. Meyer Oliver Daumke |
| author_sort | Audrey Xavier |
| collection | DOAJ |
| description | Summary: Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic growth, and induces the activation of the inflammasome pathway. hGBP1 has a unique catalytic activity to hydrolyze guanosine triphosphate (GTP) to guanosine monophosphate (GMP) in two consecutive cleavage steps. However, the functional significance of this activity in host defense remains elusive. Here, we generate a structure-guided mutant that specifically abrogates GMP production, while maintaining fast cooperative GTP hydrolysis. Complementation experiments in human monocytes/macrophages show that hGBP1-mediated GMP production is dispensable for restricting Chlamydia trachomatis growth but is necessary for inflammasome activation. Mechanistically, GMP is catabolized to uric acid, which in turn activates the NLRP3 inflammasome. Our study demonstrates that the unique enzymology of hGBP1 coordinates bacterial growth restriction and inflammasome signaling. |
| first_indexed | 2024-12-10T09:28:08Z |
| format | Article |
| id | doaj.art-7380fbad5d71493faa5a410fa2e30574 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T09:28:08Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7380fbad5d71493faa5a410fa2e305742022-12-22T01:54:28ZengElsevierCell Reports2211-12472020-05-01317hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP HydrolysisAudrey Xavier0Munir A. Al-Zeer1Thomas F. Meyer2Oliver Daumke3Crystallography, Max Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, 13125 Berlin, Germany; Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany; Department of Molecular Biology, Max-Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, GermanyDepartment of Molecular Biology, Max-Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany; Institute of Biotechnology, TIB 4/3-2, Department of Applied Biochemistry, Technical University of Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, GermanyDepartment of Molecular Biology, Max-Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, GermanyCrystallography, Max Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, 13125 Berlin, Germany; Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany; Corresponding authorSummary: Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic growth, and induces the activation of the inflammasome pathway. hGBP1 has a unique catalytic activity to hydrolyze guanosine triphosphate (GTP) to guanosine monophosphate (GMP) in two consecutive cleavage steps. However, the functional significance of this activity in host defense remains elusive. Here, we generate a structure-guided mutant that specifically abrogates GMP production, while maintaining fast cooperative GTP hydrolysis. Complementation experiments in human monocytes/macrophages show that hGBP1-mediated GMP production is dispensable for restricting Chlamydia trachomatis growth but is necessary for inflammasome activation. Mechanistically, GMP is catabolized to uric acid, which in turn activates the NLRP3 inflammasome. Our study demonstrates that the unique enzymology of hGBP1 coordinates bacterial growth restriction and inflammasome signaling.http://www.sciencedirect.com/science/article/pii/S2211124720306203cell-autonomous immunitydynamin GTPasesintracellular pathogensguanylate binding proteins |
| spellingShingle | Audrey Xavier Munir A. Al-Zeer Thomas F. Meyer Oliver Daumke hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis Cell Reports cell-autonomous immunity dynamin GTPases intracellular pathogens guanylate binding proteins |
| title | hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis |
| title_full | hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis |
| title_fullStr | hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis |
| title_full_unstemmed | hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis |
| title_short | hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis |
| title_sort | hgbp1 coordinates chlamydia restriction and inflammasome activation through sequential gtp hydrolysis |
| topic | cell-autonomous immunity dynamin GTPases intracellular pathogens guanylate binding proteins |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720306203 |
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