Non‐apoptotic functions of granzymes

Abstract

Granzymes (granule enzymes) are proteases released from cytotoxic lymphocyte granules into target cells to protect mammals from virus infection and transformed cells. Once released into the cytoplasm of the target cell, granzymes activate specific pathways to induce cell death. Although the induction of target cell death has been considered the central function for these proteases, accumulating evidence suggests that granzymes also possess additional non-death-related functions. Thus, some granzymes can achieve direct antiviral activities through the cleavage of proteins encoded by viruses as well as host factors required for the viral life cycle. The presence of elevated concentrations of circulating granzymes in various inflammatory processes and granzyme-mediated cleavage of extracellular substrates suggest that these proteases may have extracellular effects relevant to virus and tumor rejection and the pathogenesis of chronic inflammatory diseases. Here, we discuss the current knowledge of the substrates and the proposed non-apoptotic functions of granzymes, with special interest in non-death-related functions of granzymes inside the target cell.

Cleavage of La protein by granzyme H induces cytoplasmic translocation and interferes with La-mediated HCV-IRES translational activity

“…As LAK cells contain all gzms, it is not surprising that killer cells may execute potent antitranslational activities (both cap-dependent and IRES-dependent) against target cells, in a process that is independent of gzmB activity. These data, in concert with our earlier work, 13,36 strongly support the idea that the combinatorial effect of multiple gzms completely paralyzes the pathways in target cells and overcomes the effect of gzm inhibitors. Understanding the components of such paralysis remains very important.…”

“…13 As viruses have evolved multiple mechanisms to block intracellular death pathways activated by gzms, 6,13,39 the direct gzm-mediated cleavage and inactivation of viral and host proteins involved in essential viral functions may represent an important additional defense tool to suppress the intercellular dissemination of intracellular pathogens. 36 Materials and Methods Human recombinant gzms. Granzymes H, K, and M were expressed as inclusion proteins, refolded and converted into the active mature form as described.…”

Dermal-Resident versus Recruited γδ T Cell Response to Cutaneous Vaccinia Virus Infection

“…In contrast, the immigrating population of CD103 2 CCR6 2 DN gd T cells, which appeared concurrently, only upregulated granzyme B expression at a later time point. Although classically associated with cytotoxicity, which was shown for gd T cells (44), granzyme B has direct antiviral effects within cells and can cleave structural proteins when released into the extracellular matrix (45,46). Importantly for our study, extracellular granzyme B release was shown to have remodeling activity (47), potentially facilitating migration of cells into the tissue and impacting wound repair.…”

A Novel and Divergent Role of Granzyme A and B in Resistance to Helminth Infection

“…GzmA and B are best characterized from the 5 human granzymes (A, B, H, K, and M) and the 11 murine gzms (A-G, K-N) (3). GzmA and B were long thought to mainly induce apoptosis in target cells via different signaling cascades (1), but recent evidence reveals induction of necrosis by gzmA (4) and noncytotoxic intra-and extracellular proteolytic activities: gzmA and B inactivate intracellular viruses, cleave surface receptors and extracellular matrix proteins such as collagen IV facilitating leukocyte migration, and induce cell death by cellular detachment (5). Recently, gzmA/B expression was discovered in mast cells (6), macrophages (7), regulatory T cells (Treg) (8), and human B cells (9).…”