GZMK

GZMK Full Name

granzyme K (granzyme 3

GZMK Introduction

Granzyme K (GZMK) is a chymotrypsin-like serine protease of cytotoxic lymphocytes, structurally related to granzyme A but with a distinct preference for substrates bearing aromatic and aliphatic residues at the P1 position. It is highly expressed in a specialized subset of cytotoxic T cells—often termed T_Early or GZMK-positive CD8+ T cells—that expand during chronic viral infection and in some tumors, and it is also found at lower levels in plasmacytoid dendritic cells and mast cells. The human gene sits in the granzyme cluster on chromosome 5q11–q12, adjacent to GZMA and GZMH.

Figure 1. The structure of GZMK.

Inflammation-Oriented Cytotoxic Activity
GZMK is delivered into target cells through perforin pores and cleaves a broad spectrum of cytoplasmic substrates, including components of the cytoskeleton and regulators of apoptosis. Unlike granzyme B, GZMK does not efficiently activate caspases, and instead its cytotoxicity proceeds through mitochondrial disruption, ROS generation, and the leakage of inflammatory DAMPs. In the extracellular space, GZMK signals through protease-activated receptors (notably PAR-1) on endothelial cells and fibroblasts, triggering calcium flux, IL-6 and IL-8 release, and leukocyte recruitment. This dual intracellular/extracellular profile has positioned GZMK as a bridge between direct cytotoxic killing and the orchestration of inflammatory responses.

Chronic Infection, Autoimmunity, and Aging
Single-cell transcriptomic studies have repeatedly identified GZMK-high CD8+ T cells as a hallmark of immune aging and of chronic viral infections such as HIV and CMV, where they accumulate despite apparent viral control. In rheumatoid arthritis and inflammatory bowel disease, GZMK-positive T cells are enriched in inflamed tissues and their abundance correlates with disease activity, supporting a model in which GZMK-driven inflammation sustains tissue damage. GZMK has also attracted interest as a target in cancer immunotherapy, since T cells engineered to secrete GZMK may enhance tumor-cell killing while simultaneously reshaping the tumor microenvironment toward a more inflammatory state.

Alternate Names for GZMK

GZMK; granzyme K (granzyme 3; tryptase II); TRYP2; granzyme K; NK-Tryp-2; granzyme 3; granzyme-3; tryptase II; fragmentin-3; NK-tryptase-2; granzyme K (serine protease, granzyme 3; tryptase II);