Are all granzymes cytotoxic in vivo?

Lars Joeckel, Phillip Ian Bird

Research output: Contribution to journalArticleResearchpeer-review

62 Citations (Scopus)

Abstract

Abstract Granzymes are serine proteases mainly found in cytotoxic lymphocytes. The best-studied member of this group is granzyme B, which is a potent cytotoxin that has set the paradigm that all granzymes are cyototoxic. In the last five years this paradigm has become controversial. On one hand there is a plethora of sometimes contradictory publications showing mainly caspase-independent cytotoxic effects of granzyme A and the so-called orphan granzymes in vitro. On the other hand there are increasing numbers of reports of granzymes failing to induce cell death in vitro unless very high (potentially supra-physiological) concentrations are used. Furthermore, experiments with granzyme A or granzyme M knock-out mice reveal little or no deficit in their cytotoxic lymphocytes killing ability ex vivo, but indicate impairment in the inflammatory response. These findings of non-cytotoxic effects of granzymes challenge dogma, and thus require alternative or additional explanations of the role of granzymes in defeating pathogens to be developed. Here we review evidence for granzyme cytotoxicity, give an overview of their non-cytotoxic functions, and suggest technical improvements for future investigations.
Original languageEnglish
Pages (from-to)181 - 202
Number of pages22
JournalBiological Chemistry
Volume395
Issue number2
DOIs
Publication statusPublished - 2014

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