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CASP5
CASP5 Full Name
caspase 5, apoptosis-related cysteine peptidase
CASP5 Introduction
Caspase-5 is a caspase protease. Caspase is a word formed from the cysteine protease family of proteases having a cysteine residue in the protease active site, and the ability of these enzymes to cleave their substrates after aspartic acid residues. The caspase family of proteases have historically been functionally grouped into those that are caspases "central" to apoptosis (e.g. Caspase-3, -8, -9) and "other" caspases which are mediators of inflammatory processes. CASP5, along with human Caspase-1, Caspase-4 and murine Caspase-11, is considered an "inflammatory caspase". In contrast to caspases that perform an apoptotic "executor" function, the principal biological function of CASP5 is not to directly trigger or perform apoptosis. Rather, CASP5 is a dedicated sensor, uniquely evolved to recognize and respond to "danger" signals from pathogens present in the cytosol, such as lipopolysaccharide (LPS), the primary component of the cell wall of Gram-negative bacteria. The LPS recognition mechanism is the core of what has been termed the "non-canonical inflammasome" pathway. CASP5 is found in the cytosol in its unstimulated state as an inactive proenzyme, or pro-caspase-5. Direct recognition and binding of intracellular LPS by the CARD domain of CASP5 causes oligomerization and auto-catalytic cleavage of CASP5 molecules into the active enzyme and downstream events. This is why if Gram-negative bacteria release LPS into the cytosol of the host cell (for example by escaping from the phagosome) the CARD domain of CASP5 directly binds to the lipid A portion of LPS, which results in conformational changes and CASP5 activation.
Figure 1. Structures of the human caspase-5 gene, mRNAs and proteins. (Source: Eckhart L, et al. 2024)
Activated CASP5 has a protease activity, and the main substrate of CASP5 is the protein Gasdermin D (GSDMD). CASP5 cleaves GSDMD at the linker between the N-terminal and C-terminal domains, releasing the active N-terminal fragment (GSDMD-N). GSDMD-N quickly oligomerizes and inserts into the cell membrane, where it forms membrane pores of 10-15 nm in diameter. GSDMD pore formation causes loss of membrane integrity, which dissipates ionic gradients, causes cell swelling, and eventually leads to lytic rupture of the cell in a form of inflammatory cell death known as "pyroptosis". Pyroptosis functions to both eliminate the infected cell and also to release a flood of inflammatory mediators and damage-associated molecular patterns (DAMPs), including the pro-forms of IL-1β and IL-18, and ATP, which together help to recruit additional immune cells and perpetuate the inflammatory response. In addition to these mechanisms, activated CASP5 can also promote, in an indirect manner, the activation of the canonical inflammasome (e.g., NLRP3 inflammasome). Potassium efflux through GSDMD pores can provide amplification signals for further IL-1β and IL-18 maturation and release, amongst other signals, in a complex signaling network.
In infectious diseases, the activation of CASP5 has both beneficial and detrimental effects. On the one hand, it is a critical host defense response to Gram-negative bacterial infection. On the other hand, it may also lead to excessive inflammatory injury. For instance, in sepsis, systemic CASP5 activation induced by circulating LPS in blood can result in extensive pyroptosis, cytokine storms, and multiple organ failure. CASP5 is also closely associated with non-infectious inflammatory diseases. For example, in inflammatory bowel disease (IBD), including ulcerative colitis (UC), it was observed that the expression level of CASP5 was significantly positively correlated with disease activity and the severity of inflammation. High expression of CASP5 in intestinal epithelial cells may cause hyper-sensitivity to LPS produced by gut dysbiosis and further promote persistent intestinal inflammation and tissue damage.
Alternate Names for CASP5
CASP5; caspase 5, apoptosis-related cysteine peptidase; ICH-3; ICEREL-III; ICE(rel)III; caspase-5; CASP-5; TY protease; protease TY; ICE(rel)-III; protease ICH-3; caspase 5, apoptosis-related cysteine protease;
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