The Cytotoxic Lymphocyte Protease, Granzyme B, Targets the Cytoskeleton and Perturbs Microtubule Polymerization Dynamics

• Published in: The Journal of biological chemistry 2006-03, Vol.281 (12), p.8118-8125
• Main Authors: Adrain, Colin, Duriez, Patrick J., Brumatti, Gabriela, Delivani, Petrina, Martin, Seamus J.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Apoptosis; Caspases - metabolism; Cell-Free System - metabolism; Cytoskeleton - metabolism; Electrophoresis, Gel, Two-Dimensional; Enzyme Activation; Granzymes; HeLa Cells; Humans; Jurkat Cells; Killer Cells, Natural - metabolism; Microtubules - metabolism; Mitosis; Molecular Sequence Data; Protein Biosynthesis; Protein Structure, Tertiary; RNA, Small Interfering - metabolism; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T-Lymphocytes, Cytotoxic - metabolism; Time Factors; Transcription, Genetic; Tubulin - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M509361200

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 α-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.