GZMB

Official Full Name

granzyme B

Organism

Homo sapiens

GeneID

3002

Background

This gene encodes a member of the granzyme subfamily of proteins, part of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and proteolytically processed to generate the active protease, which induces target cell apoptosis. This protein also processes cytokines and degrades extracellular matrix proteins, and these roles are implicated in chronic inflammation and wound healing. Expression of this gene may be elevated in human patients with cardiac fibrosis. [provided by RefSeq, Sep 2016]

Synonyms

C11; HLP; CCPI; CGL1; CSPB; SECT; CGL-1; CSP-B; CTLA1; CTSGL1;

Bio Chemical Class

Peptidase

Protein Sequence

MQPILLLLAFLLLPRADAGEIIGGHEAKPHSRPYMAYLMIWDQKSLKRCGGFLIRDDFVLTAAHCWGSSINVTLGAHNIKEQEPTQQFIPVKRPIPHPAYNPKNFSNDIMLLQLERKAKRTRAVQPLRLPSNKAQVKPGQTCSVAGWGQTAPLGKHSHTLQEVKMTVQEDRKCESDLRHYYDSTIELCVGDPEIKKTSFKGDSGGPLVCNKVAQGIVSYGRNNGMPPRACTKVSSFVHWIKKTMKRY

Open

Disease

Aneurysm/dissection

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

Granzyme B (GZMB) is a serine protease primarily found in the cytosolic granules of cytotoxic T-cells and natural killer (NK) cells. As a member of the peptidase S1 family, GZMB plays a crucial role in immune-mediated cell death. Delivered into target cells via the immunological synapse, GZMB starts cell death by any means. Setting off an apoptotic cascade, it activates many caspases—caspase-3, -7, -9, and -10. GZMB has more recently been discovered to cut gasdermin E (GSDME), thus setting off pyroptosis, a kind of inflammatory cell death. Apart from its function in cell death, GZMB handles cytokines and breaks down extracellular matrix proteins, hence supporting chronic inflammation and wound healing mechanisms. In cardiac diseases, higher GZMB expression has been linked to fibrosis formation, indicating its role in tissue remodeling and illness advancement.

Gasdermin Family and Cell Death Mechanisms

Different family members of the Gasdermin (GSDM) family have been triggered by various proteases and stimuli, making them important mediators of pyroptotic cell death. PAMPs and DAMPs in the canonical route cause the development of inflammasome complexes, hence activating caspase-1. While the NLRC4 inflammasome is triggered by bacterial T3SS components via NAIP proteins, the NLRP3 inflammasome reacts to other toxins and nucleic acids. Anthrax deadly toxin elicits the NLRP1 inflammasome; the AIM2 inflammasome identifies double-stranded DNA from both host and pathogen sources. Bacterial toxins and RhoA-modifying proteins activate the Pyrin inflammasome.

Caspase-11 (human caspase-4/5) activates via the non-canonical route. These activated caspases cut gasdermin D (GSDMD), producing the active N-terminal fragment that creates oligomeric holes in the plasma membrane. These holes enable potassium efflux that further drives NLRP3 inflammasome formation and helps to release inflammatory mediators including IL-1β and IL-18. The process ends in cell enlargement and NINJ1-dependent plasma membrane rupture, which releases cellular contents including LDH and DAMPs like HMGB1.

Different gasdermin family members' activation methods exhibit fascinating variety. Caspase-8 and caspase-3 respectively break GSDMC and GSDME, hence enabling the shift from apoptotic to pyroptotic cell death. GzmA and GzmB are secreted by cytotoxic cells to directly cut GSDMB and GSDME, hence causing pyroptosis. Notably, Group A Streptococcus secretes SpeB, a cysteine protease that selectively targets GSDMA, triggering pathogenic cascades leading to pyroptosis. Caspase-1 has also been shown to cut many gasdermin family members including GSDMB, GSDMA, and GSDME.

Figure 1 describes the molecular mechanisms of gasdermin activation, detailing how microbial invasion triggers canonical and non-canonical inflammasomes to activate inflammatory caspases, leading to the cleavage of GSDMD and the formation of GSDMD pores. Figure 1. Molecular mechanisms of gasdermins activation. (Zhu C, et al., 2024)

Therapeutic Implications and Future Directions

Particularly in conditions like sepsis, viral infections, and cancer, the therapeutic promise of aiming for gasdermin-mediated cell death has attracted much interest. Current approaches mostly concentrate on blocking GSDMD using many methods, including direct binding, cleavage prevention, or N-terminal oligomerization suppression. Still, in the sector, certain major issues are unsolved.

The role of GSDMD varies significantly across different cell types and physiological contexts. GSDMD activation in macrophages worsens inflammation and increases sepsis death. In epithelial cells, however, it is very important to preserve intestinal mucosal homeostasis. Therapeutic targeting is complicated by this context-dependent function. Though several proteases able to cut GSDMD have been found, including apoptotic caspases, neutrophil elastase, and cathepsin G, the exact methods of detection and cleavage are still unknown.

Specific GSDMD inhibitors' therapeutic usefulness is limited by off-target effects and unknown toxicological repercussions, which complicate their development. Moreover, GSDMD's non-pyroptotic activities and the management of its activation regulating either lytic cell death or regulated responses without cell death are still not well-known. Knowing the molecular pathways of hole creation and cell lysis during pyroptosis might provide novel treatment ideas, including the possible targeting of NINJ1.

Recent developments in knowledge of pannexin-1 cleavage by caspase-11 and its involvement in ATP release and P2X7-related cell death have provided new possibilities for therapeutic intervention. The intricate interaction between several cell death pathways and their regulatory systems implies that effective treatment approaches would have to aim at many elements of these pathways at the same time while preserving tissue-specific effects.

The interconnectedness of GZMB and gasdermin-mediated cell death pathways poses a difficult but interesting target for therapeutic intervention. Research is still revealing the complex interactions between these pathways and their activities in different disorders, which may lead to novel treatment ideas that might properly attack these processes and reduce negative consequences on normal physiological functioning. The difficulty is creating selective inhibitors that can control these pathways in a context-dependent fashion while preserving their advantageous functions in host defense and tissue homeostasis.

References:

Zhu C, Xu S, Jiang R, Yu Y, Bian J, Zou Z. The gasdermin family: emerging therapeutic targets in diseases. Signal Transduct Target Ther. 2024;9(1):87.
Gleave A, Granville DJ. Granzyme B in Autoimmune Skin Disease. Biomolecules. 2023;13(2):388. Published 2023 Feb 18.
Russo V, Klein T, Lim DJ, et al. Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction. Sci Rep. 2018;8(1):9690.

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