canonical inflammasome complex

Definition

Target type: cellularcomponent

A cytosolic protein complex that is capable of activating caspase-1. [GOC:dph, PMID:17599095]

The canonical inflammasome complex is a multi-protein complex that plays a central role in innate immunity by sensing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) and triggering the production of inflammatory cytokines, such as IL-1β and IL-18. The core components of the canonical inflammasome complex include a sensor protein, an adaptor protein called ASC, and the effector protein caspase-1.

**Sensor proteins:**

* **NLRP3:** The most well-characterized inflammasome sensor, activated by a wide range of stimuli, including bacterial toxins, viral components, crystalline substances, and cellular stress.

* **NLRC4:** Activated by flagellin, bacterial type III secretion systems, and cytosolic DNA.

* **AIM2:** Activated by cytosolic double-stranded DNA, a common product of viral infection.

**ASC:**

* Acts as an adaptor protein, bridging the sensor protein to caspase-1.
* Contains a pyrin domain that interacts with the sensor protein and a caspase recruitment domain (CARD) that interacts with caspase-1.
* Forms a large oligomeric structure called the "speck", which serves as a scaffold for the assembly of the inflammasome complex.

**Caspase-1:**

* A cysteine protease that is activated by the inflammasome complex.
* Cleaves pro-IL-1β and pro-IL-18 into their mature forms, which are then secreted into the extracellular space.
* Also involved in the processing of other inflammatory mediators, such as Gasdermin D, which triggers pyroptosis, a form of programmed cell death.

**Cellular component:**

The inflammasome complex is typically assembled in the cytosol of cells. The sensor proteins are located in the cytoplasm, while ASC and caspase-1 are recruited to the sensor protein upon activation. Once assembled, the inflammasome complex can form a large, multi-protein complex called the "speck", which is visible by microscopy.

**Mechanism of action:**

Inflammasome activation typically follows a two-step process:

1. **Priming:** The cells are primed for inflammasome activation by signaling pathways that induce the expression of pro-IL-1β and pro-IL-18, as well as other inflammasome components.
2. **Activation:** The sensor protein is activated by specific stimuli, leading to the recruitment of ASC and caspase-1 and the formation of the inflammasome complex.

**Regulation:**

The activity of the inflammasome complex is tightly regulated to prevent excessive inflammation and tissue damage. Multiple mechanisms are involved in regulating inflammasome activation, including:

* **Negative regulators:** Several proteins, such as the NLRP3 inflammasome inhibitor (NLRP3i), act as negative regulators of inflammasome activation.
* **Ubiquitination and degradation:** Inflammasome components can be ubiquitinated and targeted for degradation by proteasomes.
* **Apoptosis-associated speck-like protein containing a CARD (ASC) cleavage:** Caspase-8 can cleave ASC, preventing the formation of the inflammasome complex.

**Pathological implications:**

Dysregulation of inflammasome activation can contribute to the development of various inflammatory diseases, including:

* **Autoinflammatory diseases:** such as cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), and Muckle-Wells syndrome (MWS).
* **Infectious diseases:** such as sepsis, meningitis, and pneumonia.
* **Neurodegenerative diseases:** such as Alzheimer's disease and Parkinson's disease.
* **Metabolic diseases:** such as type 2 diabetes and atherosclerosis.

**Therapeutic potential:**

Targeting the inflammasome complex has emerged as a promising therapeutic strategy for various inflammatory diseases. Several approaches are being investigated, including:

* **Small-molecule inhibitors:** Targeting the sensor protein or caspase-1 activity.
* **Antibodies:** Blocking the interaction of ASC with other inflammasome components.
* **Gene therapy:** Suppressing the expression of inflammasome components.

**Conclusion:**

The canonical inflammasome complex plays a crucial role in innate immunity by sensing pathogens and danger signals, triggering the production of inflammatory cytokines, and initiating pyroptosis. Dysregulation of inflammasome activation contributes to various inflammatory diseases, making it a promising therapeutic target.'
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