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First published online February 22, 2006
doi: 10.1242/10.1242/jcs.02791

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Identification of -tubulin as a granzyme B substrate during CTL-mediated apoptosis

¹ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7
² Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7

^* Author for correspondence (e-mail: chris.bleackley{at}ualberta.ca)

Accepted 14 November 2005

Cytotoxic lymphocytes induce target cell apoptosis via two major pathways: Fas/FasL and granule exocytosis. The latter pathway has largely been defined by the roles of the pore-forming protein perforin and by the serine proteinases granzymes A and B. Upon entry into target cells, the granzymes cleave substrates that ultimately result in cell death. To gain further insight into granzyme B function, we have identified novel substrates. SDS-PAGE analysis of S100 cell lysates identified a 51 kDa protein that was cleaved by granzyme B. Mass spectrometry analysis revealed that this fragment was the microtubule protein, -tubulin, which was confirmed by western blotting. In addition, two-dimensional gel analysis showed that the truncated form of -tubulin had a more basic isoelectric point than the full-length molecule, suggesting that granzyme B removed the acidic C-terminus. Site-directed mutagenesis within this region of -tubulin revealed the granzyme B recognition site, which is conserved in a subset of -tubulin isoforms. Significantly, we showed that -tubulin was cleaved in target cells undergoing apoptosis as induced by cytotoxic T lymphocytes. Therefore, in addition to its role in the activation of mitochondria during apoptosis, these results suggest a role for granzyme B in the dismantling of the cytoskeleton.

Key words: Apoptosis, Tubulin, Cytotoxic lymphocyte

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