Serpins prevent granzyme-induced death in a species-specific manner.
Expression of serine protease inhibitors (serpins) is one of the mechanisms used by tumour cells to escape immune surveillance. Previously, we have shown that expression of serpins SPI-6 and SPI-CI, respectively, renders tumour cells resistant to granzyme B (GrB)-mediated death and granzyme M (GrM)-mediated death. To obtain better insight into the interaction between serpins and their target proteases, we investigated the roles of protease inhibitor (PI)-9 and SPI-6 in the resistance to GrB-mediated and CD95-mediated death in further detail. Neither human PI-9 nor its murine orthologue SPI-6 was capable of preventing CD95-induced apoptosis in murine or human cells, indicating that these serpins do not inhibit the activation of apical caspases in this pathway. High expression of PI-9 or SPI-6 did prevent apoptosis induced by human GrB. Strikingly, only SPI-6, and not PI-9, was capable of inhibiting murine GrB, suggesting that a difference in enzymatic specificity exists between the mouse and the human granzymes. In agreement with this suggestion, murine GrB was clearly less effective in inducing apoptosis in human cells. Similar species specificity was also observed for SPI-CI and GrM when either their capacity to associate or the effectiveness of GrM-induced cytotoxicity was analysed. Our findings therefore indicate a species diversity that has a clear effect on mixed in vitro effector target settings.
Bots
Michael
M
Laboratory of Experimental Oncology and Radiobiology, Amsterdam Medical Center, Amsterdam, The Netherlands.
VAN Bostelen
Liesbeth
L
Rademaker
Mirjam Tga
MT
Offringa
Rienk
R
Medema
Jan Paul
JP
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D053804:Granzymes; D006801:Humans; D051379:Mice; D012697:Serine Endopeptidases / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000502:physiology; D015843:Serpins / Q000378:metabolism* / Q000502:physiology*
D015842:Serine Proteinase Inhibitors; D015843:Serpins; C509213:GZMB protein, human; C509218:GZMM protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; C509219:Gzmm protein, mouse; D012697:Serine Endopeptidases