Granzyme B substrates (GZMB substrates)

Granzyme B substrates are a diverse group of intracellular proteins within target cells that are proteolytically cleaved by the serine protease Granzyme B (GZMB) to execute programmed cell death. This mechanism is a fundamental component of the adaptive immune response, where cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells deliver GZMB into target cells via perforin-mediated pores [UniProt, P10144]. Once inside the cytoplasm, GZMB cleaves specific substrates after aspartic acid residues, most notably the pro-apoptotic Bcl-2 family member Bid and executioner caspases such as Caspase-3 and Caspase-7 [PubMed, 11526337]. The cleavage of Bid into truncated Bid (tBid) triggers mitochondrial outer membrane permeabilization and the release of cytochrome c, while the activation of Caspase-3 leads to the degradation of structural proteins and the activation of Caspase-Activated DNase (CAD) through the cleavage of its inhibitor, ICAD [PubMed, 10358168]. In clinical oncology, these substrates serve as the functional endpoints for various immunotherapies, including immune checkpoint inhibitors and CAR-T cell therapies, which aim to enhance the delivery of GZMB to malignant cells [PubMed, 15123777]. Therapeutic challenges include the potential for off-target effects leading to systemic inflammation or the development of resistance through the upregulation of endogenous inhibitors like Serpin B9 [PubMed, 10660615].

Other names

Granzyme-2 substratesFragmentin-2 substratesCTLA1 substratesCytotoxic T-lymphocyte proteinase 2 substratesGZMB targets

Proteolytic cleavage of pro-apoptotic proteins including Bid, Caspase-3, and ICAD, leading to mitochondrial dysfunction and DNA fragmentation.