A ‘polarized’ look at α-tubulin cleavage by granzyme B

Abstract

Granzyme B-induced apoptosis is one mechanism by which cytotoxic lymphocytes kill tumour or virus infected cells. As such, identifying critical substrates for granzyme B is of great interest with respect to mechanisms of cytotoxic lymphocyte (cytotoxic T lymphocytes (CTL) and natural killer (NK))-induced cell death and our general understanding of how cytototoxic lymphocytes (CL) protect the body from cancer and infection. The concerted effort of several labs has identified a number of granzyme B substrates that when cleaved promote apoptosis1, 2, 3, 4, 5, 6, 7 (Figure 1). Granzyme B has also been shown to cleave proteins for which an effect on cell death has not been shown.8, 9, 10, 11 It is unclear if granzyme B preferentially targets one or a few critical substrates or if granzyme B exerts its full effect by cleaving several substrates. Adding to this complexity, human and mouse granzyme B have been shown to target different substrates in vitro12 and are selectively blocked by different inhibitors. It is unclear if human and murine granzyme B preferentially target the same critical substrates or if these granzymes target diverse substrates, several of which overlap.