Key Points
GrB-induced intracellular cleavage and phosphorylation events do not need perforin.
These cleavages and phosphorylations require GrB enzyme activity.
DDR and IRF-3 phosphorylation are some of the functional results of these events.
Abstract
Granzyme B (GrB) is an immune protease implicated in the pathogenesis of several human diseases. In the current model of GrB activity, perforin determines whether the downstream actions of GrB occur intracellularly or extracellularly, producing apoptotic cytotoxicity or nonapoptotic effects, respectively. In the current study, we demonstrate the existence of a broad range of GrB-dependent signaling activities that 1) do not require perforin, 2) occur intracellularly, and 3) for which cell death is not the dominant outcome. In the absence of perforin, we show that GrB enzymatic activity still induces substoichiometric activation of caspases, which through nonlethal DNA damage response signals then leads to activity-associated phosphorylation of IFN regulatory factor–3. These findings illustrate an unexpected potential interface between GrB and innate immunity separate from the traditional role of GrB in perforin-dependent GrB-mediated apoptosis that could have mechanistic implications for human disease.
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Footnotes
This work was supported in part by National Institutes of Health, Office of Extramural Research Grants R01 DE 12354-15A1 and R01AR069569 and National Institutes of Health Grant T32AR048522 and by the Rheumatology Research Foundation. D.J.G. was supported by grants-in-aid from the Canadian Institutes for Health Research and the Michael Smith Foundation for Health Research. E.J.G. and E.T. are Jerome L. Greene Foundation Scholars. E.J.G. was also supported in part by a Vasculitis Foundation research award sponsored in loving memory by the family of the late Dr. Darwin James Liao. L.C.-R. was supported in part by the Stabler Foundation. The manuscript content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Canadian Institutes for Health and Research.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- CAD
- caspase-activated DNase
- DDR
- DNA damage response
- DEVD
- aspartic acid–glutamic acid–valine–aspartic acid
- ECM
- extracellular matrix
- GC
- granule content
- GrB
- granzyme B
- HSG
- human submandibular gland
- ICAD
- inhibitor of caspase-activated DNase
- IRF
- IFN regulatory factor
- PIKK
- PI3K-like kinase.
- Received May 13, 2020.
- Accepted November 11, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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