Granzyme B Induces IRF-3 Phosphorylation through a Perforin-Independent Proteolysis-Dependent Signaling Cascade without Inducing Cell Death.

Autor:	Gapud EJ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Trejo-Zambrano MI; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Gomez-Banuelos E; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Tiniakou E; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Antiochos B; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Granville DJ; International Collaboration on Repair Discoveries Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada., Andrade F; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Casciola-Rosen L; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Rosen A; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224; arosen@jhmi.edu.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224; and.; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2021 Jan 15; Vol. 206 (2), pp. 335-344. Date of Electronic Publication: 2020 Dec 07.
DOI:	10.4049/jimmunol.2000546
Abstrakt:	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. (Copyright © 2021 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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