title: The cytotoxic lymphocyte protease, granzyme B, targets the cytoskeleton and perturbs microtubule polymerization dynamics.
abstract: Granzyme B, a serine protease derived from cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell granules, plays an important role in coordinating apoptosis of CTL and NK target cells. Here, we report that granzyme B targets the cytoskeleton by cleaving and removing the acidic C-terminal tail of alpha-tubulin. Consistent with this, Granzyme B markedly enhanced rates of microtubule polymerization in vitro, most likely by removal of an autoinhibitory domain within the tubulin C terminus. Moreover, delivery of Granzyme B into HeLa target cells promoted dramatic reorganization of the microtubule network in a caspase-independent manner. These data reveal that granzyme B directly attacks a major component of the cell cytoskeleton, which may contribute to the incapacitation of target cells during CTL/NK-mediated killing.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Colin
authors.initials: C
authors.lastname: Adrain
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Duriez
authors.forename: Gabriela
authors.initials: G
authors.lastname: Brumatti
authors.forename: Petrina
authors.initials: P
authors.lastname: Delivani
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002474:Cell-Free System / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014404:Tubulin / Q000737:chemistry
chemical_list: D034741:RNA, Small Interfering; D014404:Tubulin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases