Granzyme B natural substrates (GZMB substrates)

Granzyme B natural substrates comprise a broad array of intracellular and extracellular proteins that are proteolytically processed by the serine protease Granzyme B (GZMB). In the canonical immune response, Granzyme B is released by cytotoxic T lymphocytes and natural killer cells and enters target cells via perforin-mediated pores to cleave key pro-apoptotic proteins like pro-caspase-3 and the BH3-only protein Bid (ThermoFisher, 2024). This cleavage triggers rapid programmed cell death through both caspase-dependent and mitochondrial pathways, effectively eliminating virally infected or malignant cells (Wikipedia, 2024). Additionally, Granzyme B targets nuclear proteins such as ICAD and PARP to ensure genomic fragmentation and prevent DNA repair (NIH/PubMed, 2024). Beyond its intracellular role, Granzyme B also acts in the extracellular space, where it cleaves various extracellular matrix (ECM) components, including fibronectin, vitronectin, and aggrecan, as well as pro-inflammatory cytokines like IL-1α (Thompson & Cao, 2024). These extracellular activities are implicated in tissue remodeling, chronic inflammation, and the pathogenesis of autoimmune diseases and impaired wound healing (Frontiers in Immunology, 2024). Because Granzyme B lacks a potent endogenous inhibitor in the extracellular milieu, its activity can become dysregulated, leading to excessive tissue damage. Consequently, therapeutic research focuses on developing specific Granzyme B inhibitors to treat inflammatory conditions or engineering Granzyme B-based fusion proteins for targeted cancer therapy (TandfOnline, 2024).

Other names

GZMB substratesGranzyme-2 substratesCytotoxic T-lymphocyte proteinase 2 substratesCTLA-1 substrates

Proteolytic cleavage at specific aspartic acid residues, leading to the activation of pro-apoptotic cascades or the degradation of structural and signaling proteins.