caspase 4 (apoptosis-related cysteine 鈥嬧?媝eptidase): a potential drug target and biomarker

Target Name: CASP4

NCBI ID: G837

CASP4

caspase 4 (apoptosis-related cysteine 鈥嬧?媝eptidase): a potential drug target and biomarker

Introduction

Apoptosis, the natural cell death process, plays a crucial role in various biological processes, including development, growth, and maintenance of tissue homeostasis. Cellular stress, DNA damage, and external environmental stimulation and other factors may cause cell apoptosis. Apoptosis is the basis of normal life activities of organisms and an important means to resist interference from various external factors. However, when cell apoptosis is excessive or cannot be regulated normally, it may cause a series of diseases, such as tumors, neurodegenerative diseases, etc. Therefore, studying the regulatory mechanism of apoptosis and revealing potential drug targets are of great clinical significance.

CASP4, full name caspase 4, is an apoptosis-related cysteine 鈥嬧?媝eptidase that plays an important role in the body and is an important component in the apoptosis signal transduction pathway. In multiple cell types, CASP4 plays a key role in the regulation of apoptosis. This article aims to explore the role of CASP4 in apoptosis and tumorigenesis, and to provide new targets and biomarkers for drug development.

Discovery and structure of CASP4

CASP4 is a calcine-containing serine protease that belongs to the apoptosis-related cysteine 鈥嬧?媝eptidase family. Its name comes from the characteristic calcine group in its molecule. CASP4 mainly acts on the Bax protein in the apoptosis signaling pathway in vivo, regulating the process of apoptosis by inhibiting the activation of Bax.

The molecular structure of CASP4 shows that it has an N-terminal asymmetric amino acid residue, which plays a key role in the function of CASP4. In addition, the C-terminus of CASP4 also has a conserved structural domain, which is important for the function of CASP4 in vivo.

The role of CASP4 in the regulation of apoptosis

CASP4 plays multiple roles in the regulation of apoptosis, including:

1. Regulate the activity of Bax protein

Bax protein is a key molecule in the apoptosis signaling pathway and plays an important role in the apoptosis process. CASP4 can regulate the process of apoptosis by inhibiting the activation of Bax protein. Studies have found that the inhibitory effect of CASP4 can be achieved by reducing the phosphorylation level of Bax protein. In addition, CASP4 can also affect the activity of Bax protein by regulating its ubiquitination modification.

2. Regulate cell cycle

The cell cycle is an important process of cell growth and division, and is also an important regulatory factor in cell apoptosis. CASP4 also plays an important role in the cell cycle. Studies have found that CASP4 can inhibit the formation of spindles, thereby inhibiting the progression of cell mitosis. In addition, CASP4 can also affect the stability of the spindle by regulating the phosphorylation level of spindle tubulin in the cell cycle, thereby affecting the cell cycle.

3. Participate in the regulation of apoptosis

The regulation of apoptosis is a complex process, in which CASP4 also plays an important role. Studies have found that CASP4 can regulate the process of apoptosis and affect the occurrence of apoptosis by regulating the activity of Bax protein. In addition, CASP4 can also affect the occurrence of apoptosis by regulating the activity of other apoptosis-related molecules in cells, such as the apoptosis inducer BIM.

The role of CASP4 in tumorigenesis

CASP4 also plays an important role in tumorigenesis. Studies have found that the expression level of CASP4 is closely related to tumorigenesis. In various tumor types, the expression level of CASP4 is significantly higher than that in normal tissues. In addition, the expression level of CASP4 is also related to the invasion and metastasis ability of tumors.

Application of CASP4 in drug development

CASP4 has broad application prospects in drug research and development. First, by inhibiting the activity of CASP4, we can

Protein Name: Caspase 4

Functions: Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:34671164, PubMed:32109412). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:7797510, PubMed:23516580, PubMed:26375003, PubMed:32109412). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:7797510, PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590, PubMed:32109412). Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B and IL18 (PubMed:25121752, PubMed:25119034, PubMed:26375003, PubMed:31268602, PubMed:32109412). In the non-canonical inflammasome, CASP4 is activated by direct binding to LPS without the need of an upstream sensor (PubMed:25121752, PubMed:25119034, PubMed:29520027). LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD, followed by pyroptosis of infected cells and their extrusion into the gut lumen (PubMed:25121752, PubMed:25119034). Also indirectly promotes secretion of mature cytokines (IL1A, IL18 and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin (PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988, PubMed:26174085, PubMed:26508369). Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B and IL18 secretion (PubMed:33377178). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:25964352). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752, PubMed:26375003, PubMed:25964352). May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC) (By similarity). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Catalyzes cleavage and maturation of IL18 (PubMed:15326478). In contrast, it does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590)

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•   general information;
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•   protein biological mechanisms;
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•   the target screening and validation;
•   expression level;
•   disease relevance;
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The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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