Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

Susanto, O., Stewart, S. E., Voskoboinik, I., Brasacchio, D., Hagn, M., Ellis, S., Asquith, S., Sedelies, K. A., Bird, P. I., Waterhouse, N. J. and Trapani, J. A. (2013) Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. Cell Death and Differentiation, 20 9: 1183-1193. doi:10.1038/cdd.2013.59


Author Susanto, O.
Stewart, S. E.
Voskoboinik, I.
Brasacchio, D.
Hagn, M.
Ellis, S.
Asquith, S.
Sedelies, K. A.
Bird, P. I.
Waterhouse, N. J.
Trapani, J. A.
Title Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis
Journal name Cell Death and Differentiation   Check publisher's open access policy
ISSN 1350-9047
1476-5403
Publication date 2013-09
Sub-type Article (original research)
DOI 10.1038/cdd.2013.59
Open Access Status
Volume 20
Issue 9
Start page 1183
End page 1193
Total pages 11
Editor P. Vandenabeele
Collection year 2014
Language eng
Formatted abstract
Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, ‘worm-like’ morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death ‘athetosis’. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes.
Keyword Granzyme
Cell death
Cytotoxic lymphocyte
Natural killer cells
Cytoskeleton
Target-cells
Cytotoxic lymphocytes
Mediated cytotoxicity
Cytolytic leukocytes
Effector molecules
Caspase activation
Rapid induction
Plasma-membrane
Natural-killer
Deficient mice
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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