Granzyme B substrate (GZMB substrate)

Granzyme B substrates in the target cell cytosol are a collection of proteins that undergo proteolytic cleavage by the serine protease Granzyme B to induce programmed cell death (UniProt P10144). This process is a critical component of the adaptive immune response, where cytotoxic T lymphocytes and natural killer cells eliminate infected or malignant cells (PubMed: 21074468). Major substrates include pro-caspases, such as Caspase-3 and Caspase-7, which are directly activated to execute the apoptotic program (PubMed: 20159594). Additionally, Granzyme B cleaves the pro-apoptotic protein Bid into its active form, tBid, which promotes mitochondrial outer membrane permeabilization and the release of cytochrome c. Other targets include the inhibitor of caspase-activated DNase (ICAD), leading to genomic DNA fragmentation, and various cytoskeletal proteins. In the context of oncology, the failure of Granzyme B to effectively cleave these substrates often contributes to immune evasion and therapeutic resistance. While these substrates are not typically the direct targets of small molecule drugs, their activation is the ultimate goal of many immunotherapies, including immune checkpoint inhibitors and CAR-T cell therapies. Monitoring the cleavage of these substrates, such as Caspase-3, serves as a vital biomarker for assessing the efficacy of T-cell mediated killing in clinical and research settings.

Other names

Caspase-3Caspase-7BidICADPARPDFF45Lamin BGranzyme B targetsCytosolic granzyme B substrates

Proteolytic activation of apoptotic signaling cascades