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Review
. 2021 Sep 16;17(9):e1009818.
doi: 10.1371/journal.ppat.1009818. eCollection 2021 Sep.

Noncytotoxic functions of killer cell granzymes in viral infections

Lisanne C de Jong  1   2 , Sandra Crnko  2 , Toine Ten Broeke  2 , Niels Bovenschen  2   3
Affiliations
Review

Noncytotoxic functions of killer cell granzymes in viral infections

Lisanne C de Jong et al. PLoS Pathog. .

Abstract

Cytotoxic lymphocytes produce granules armed with a set of 5 serine proteases (granzymes (Gzms)), which, together with the pore-forming protein (perforin), serve as a major defense against viral infections in humans. This granule-exocytosis pathway subsumes a well-established mechanism in which target cell death is induced upon perforin-mediated entry of Gzms and subsequent activation of various (apoptosis) pathways. In the past decade, however, a growing body of evidence demonstrated that Gzms also inhibit viral replication and potential reactivation in cell death-independent manners. For example, Gzms can induce proteolysis of viral or host cell proteins necessary for the viral entry, release, or intracellular trafficking, as well as augment pro-inflammatory antiviral cytokine response. In this review, we summarize current evidence for the noncytotoxic mechanisms and roles by which killer cells can use Gzms to combat viral infections, and we discuss the potential thereof for the development of novel therapies.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Schematic overview of the noncytotoxic functions of Gzms in viral infection.
CLs secrete perforin and Gzms into the immunological synapse. Perforin pores mediate Gzm entry in the target cell (1). Gzms cleave and (in)activate viral proteins (2) and host cell proteins inside the cytoplasm and the nucleus necessary for viral entry (3), replication, protein synthesis, virion assembly (4), and viral release (5). CLs and also other cell types (e.g., macrophages) can directly secrete Gzms in the microenvironment. These extracellular Gzms can induce pro-inflammatory cytokine release by multiple cell types, such as monocytes, macrophages, DCs, mast cells, fibroblasts, and epithelial cells, further supporting the antiviral immune response (6). Created with BioRender.com. CL, cytotoxic lymphocyte; DC, dendritic cell; Gzm, granzyme.
See this image and copyright information in PMC

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Grants and funding

The authors received no specific funding for this work.