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Return of the first inflammasome
Elucidation of NLRP1 inflammasome activation by p38-mediated phosphorylation and ubiquitination

dc.contributor.advisorSchmidt, Florian Ingo
dc.contributor.authorJenster, Lea-Marie
dc.date.accessioned2024-01-31T11:02:45Z
dc.date.issued30.01.2024
dc.identifier.urihttps://hdl.handle.net/20.500.11811/11284
dc.description.abstractThe assembly of inflammasomes is linked to the detection of pathogens and other danger signals by intracellular pattern-recognition receptors of the mammalian innate immune system. The human inflammasome sensor NLRP1 is activated by N-terminal proteolytic cleavage and subsequent degradation, causing the release of the C-terminal NLRP1UPA-CARD fragment and the recruitment of the adaptor protein ASC and caspase-1, resulting in the processing of IL-1β/IL-18 and pyroptotic cell death.
To study NLRP1 inflammasomes, I characterized HEK 293T and N/TERT-1 keratinocyte inflammasome reporter cell lines, and I identified two NLRP1PYD-specific nanobodies which, combined with the E3 ligase receptor VHL, allowed the precise stimulation of endogenous NLRP1 by targeted NLRP1PYD ubiquitination and subsequent N-terminal degradation.
Using the reporter cell lines, I found that various stimuli of the ribotoxic stress response activate human NLRP1 in a p38-dependent manner. In addition, infection with alphaviruses, including Semliki Forrest virus and Chikungunya virus, caused p38-dependent NLRP1 activation. p38 kinases directly phosphorylate the N-terminal linker region of the inflammasome sensor, in which serine 107 represents a critical phosphorylation site. I propose that phosphorylation of the N-terminal linker generates a phospho-degron which is recognized by cullin RING E3 ligases, causing the ubiquitination of NLRP1PYD, N-terminal degradation, and inflammasome assembly.
In addition to delineating p38-mediated NLRP1 activation, I identified novel viral NLRP1 stimuli and established lymphocytes as NLRP1-competent cell types.
en
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectInflammasome
dc.subjectNLRP1
dc.subjectNanobodies
dc.subjectribotoxischer Stress
dc.subjectp38
dc.subjectAlphavirus
dc.subjectRotavirus
dc.subjectT Zellen
dc.subjectInflammasomes
dc.subjectribotoxic stress
dc.subjectT cells
dc.subject.ddc570 Biowissenschaften, Biologie
dc.titleReturn of the first inflammasome
dc.title.alternativeElucidation of NLRP1 inflammasome activation by p38-mediated phosphorylation and ubiquitination
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsembargoedAccess
dc.date.embargoEndDate01.02.2026
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-74405
dc.relation.doihttps://doi.org/10.1084/jem.20220837
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID7440
ulbbnediss.date.accepted11.01.2024
ulbbnediss.instituteMedizinische Fakultät / Institute : Institut für Angeborene Immunität
ulbbnediss.fakultaetMedizinische Fakultät
dc.contributor.coRefereeGarbi, Natalio
ulbbnediss.contributor.orcidhttps://orcid.org/0000-0001-8580-4590


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