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Fig. 5 | Molecular Neurodegeneration

Fig. 5

From: The role of inflammasomes in vascular cognitive impairment

Fig. 5

A schematic diagram illustrating the assembly of the canonical and non-canonical inflammasome complexes. The formation of the canonical inflammasome complex requires the activation of inflammasome receptors from the second signal. As the LRR inhibitory unit unfolds from the NACHT domain, the receptors are in an “open” structure for homotypic oligomerization through their NACHT domain. Subsequently, the PYD domain recruits the adaptor protein via the PYD domain on ASC. As numerous ASC adaptor proteins comes together, they will form a filamentous structure with their CARD domain exposed. Consequently, effector proteins with their CARD domain can bind to the filamentous structure via CARD-CARD interactions. Such protein aggregation triggers proximity-induced activation of total caspase-1, and − 8, leading to cleavage of the inter-domain linker between the large and small units, producing active cleaved caspase-1 and -8. The above mentioned ASC-dependent binding mechanism generally applies to all inflammasome complexes. However, NLRP1 can form an inflammasome complex without the adaptor ASC. Using its C-terminal CARD domain, NLRP1 binds to the effector protein via the CARD-CARD domain. NLRC4 can also adopt the same ASC-independent binding mechanisms with the CARD domain on the receptor. In the non-canonical inflammasome pathway, caspase-11 can undergo homo-oligomerization in the absence of a receptor and adaptor protein component via the CARD-CARD domain interaction. Similar to the activation of total caspase-1 and -8, cleaved caspase-11 is produced upon proximity-induced activation. Abbreviations: NLR, nucleotide-binding oligomerization domain-like receptor; NACHT, NAIP (neuronal apoptosis inhibitor protein) C2TA (class 2 transcription activator, of the MHC) HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1); LRR, leucine-rich repeat; PYD, pyrin domain; CARD, caspase recruitment domain; NLRP1, NLR family pyrin domain containing 1; NLRP3, NLR family pyrin domain containing 3; NLRC4, NLR family CARD domain-containing protein 4; AIM2, absent in melanoma 2; HIN200, hematopoietic interferon-inducible nuclear proteins with a 200-amino-acid repeat; dsDNA, double-stranded DNA; ASC, apoptosis-associated speck-like protein containing a CARD; DED, death effector domain

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