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.
Highlights
One way in which cytotoxic T lymphocyte (CTL)/Natural Killer (NK) cells induce apoptosis of their targets is by exocytosis of specialized secretory granules, known as cytotoxic lymphocyte (CL) granules, in the vicinity of target cells [2, 4]
Identification of ␣-Tubulin as a Novel GzmB Target—To identify novel substrates of the CTL/NK protease GzmB, we utilized an in vitro assay in which cell-free extracts generated from Jurkat T lymphocytes were incubated with purified GzmB [16]
Taken together with the in vitro data, these data suggest that GzmB-catalyzed removal of the ␣-tubulin tail perturbs normal microtubule networks and that this may contribute to the inactivation of target cells during CTL/NK-mediated killing
Summary
One way in which CTL/NK cells induce apoptosis of their targets is by exocytosis of specialized secretory granules, known as cytotoxic lymphocyte (CL) granules, in the vicinity of target cells [2, 4]. Identification of ␣-Tubulin as a Novel GzmB Target—To identify novel substrates of the CTL/NK protease GzmB, we utilized an in vitro assay in which cell-free extracts generated from Jurkat T lymphocytes were incubated with purified GzmB [16].
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