Caspase-1: Molecular Mechanisms, Inflammatory Regulation, and Therapeutic Implications in Innate Immunity and Disease

Structural Biology and Proteolytic Activation of Caspase-1: From Zymogen to Active Inflammatory Mediator

Initially recognized as converting enzyme (ICE) Caspase‐1 is produced as a zymogen known as pro-caspase‐ weighing around 45 kDa in size. The structure of this protein includes a CARD (also known as caspase recruitment domain), at its N terminal section alongside a subunit of 20 kDa and a smaller subunit of about 10 kDa. The activation process entails cleavage at aspartate sites leading to removal of the CARD domain and formation of a heterotetramer consisting of two dimers – one with a combination of two p20 portions and another, with two p10 segments. Analysis using X ray crystallography has shown that the active site includes a cysteine residue, in the pattern that plays a crucial role in its catalytic function. This rearrangement of structure results, in the formation of the site groove required for identifying substrates and carrying out functions.

Inflammasome-Dependent Regulation of Caspase-1: Assembly, Activation, and Post-translational Modifications

The activation of caspase-1 happens within complexes known as inflammasomes that act as platforms, for immune responses. Different sensors in inflammasomes like NLRP3, NLRC four and AIM2 can lead to the assembly of inflammasomes when exposed to patterns from pathogens and dangers. During the assembly process ASC adaptor proteins polymerize based on nucleation forming speck structures that bring in and concentrate caspase-1 molecules. This clustering helps in the self-start of caspase-1 due to proximity. Several new researchers have found changes that happen after protein translation such, as phosphorylation and ubiquitination that delicately adjust caspase activity and control inflammasome reactions. These mechanisms have implications for developing treatments, for conditions.

Caspase-1-Mediated Processing of IL-1β and IL-18: Mechanisms and Physiological Consequences in Inflammatory Response

One important role of caspase-2 is to break down inflammatory proteins, like pro-interleukin 1beta and pro-interleukin 18 into their fully formed and functional versions using specific aspartate molecules such as Aspartate 116 for pro interleukin 1beta and Aspartate 36 for pro-interleukin 18. These developed cytokines are then set free through methods like pyroptosis and unconventional release pathways. After they are released into the system these cytokines trigger reactions by attaching to the right receptors present, in target cells. IL‐1beta promotes fever and widening of blood vessels and attracts a type of white blood cell called neutrophils into the affected area; meanwhile IL‐18 triggers the production of IFN gamma and boosts the immune response of natural killer cells and T cells, in the body’s defense system. It is vital to control this process since irregular cytokine release can lead to a range of inflammatory illnesses such, as autoinflammatory disorders and persistent inflammatory conditions.

Pyroptotic Cell Death Pathways: Role of Caspase-1 in Gasdermin D Cleavage and Inflammatory Cell Death

The role of Caspase-1 is crucial, in pyroptosis. A type of programmed cell demise where Gasdermin D (abbreviated as GSDMD) serves as a critical element that undergoes cleavage at Aspartic Acid 275, by Casapse-1 to detach its pore formative section from its self-inhibitory C-terminal portion during this process The isolated N-terminal segment combines into oligomers and embeds itself in the plasma membrane to create channels that disrupt cellular ion balances and eventually cause cell breakdown. In this procedure substances are freed up such as cytokines and alarm triggers that intensify inflammation reactions. New studies indicate that pyroptosis plays a role, in the natural defense system to eradicate pathogens and manage infections. Much pyroptosis may lead to harm, in tissues and abnormal inflammation.

Therapeutic Targeting of Caspase-1 in Inflammatory Diseases: Current Strategies and Future Perspectives

Due to its role in triggering inflammation reactions within the body system‌‌‌‌‍‌‌‌‍‍‍ caspase-1۱ is being considered as a target for treating various inflammatory ailments. Thus, different methods have been devised to control the activity of caspase-1 which include the use of small molecule inhibitors peptide-based inhibitors and biologics that target either the initial activators or subsequent effectors of this enzyme. The trials involving VX-765, a specific inhibitor of caspase-1 have indicated its potential, in managing epilepsy and other inflammatory disorders. New approaches aiming to interfere with the formation of inflammasomes or modulate pyroptosis are also currently being investigated. In recent times progress, in understanding the structure of molecules and designing drugs has enabled the creation of potent inhibitors that are more effective than before.

Suitable ELISA Kits

• • Caspase-1 ELISA Kit