CDC42 regulates pyrin activation under normal and disease conditions (IMAGE)
Caption
1. CDC42 regulates pyrin activation
Pyrin, an innate immune sensor, interacts with CDC42 when it detects an invading pathogen, triggering an inflammatory response. This response helps the body defend itself against the pathogen. The interaction between pyrin and CDC42 is weak under resting conditions but becomes stronger following pathogen invasion, leading to pyrin activation.
2. Comparison between normal and disease states
Upper panel: Under normal conditions, pyrin and CDC42 interact only weakly. In response to pathogen invasion, they assemble into clusters, leading to pyrin activation.
Middle panel: With inflammation-associated CDC42 variants, the interaction between pyrin and CDC42 is enhanced, promoting cluster formation.
Lower panel: With familial Mediterranean fever (FMF)-associated pyrin variants, the interaction between pyrin and CDC42 is enhanced, likewise promoting cluster formation.
As a result, even minor stimuli can trigger excessive inflammation in these disorders.
3. Mechanism of pyrin activation
Left: Upon detecting an invading pathogen, pyrin interacts with CDC42, and the two proteins assemble into clusters. These clusters promote the assembly of an inflammasome, a multiprotein complex that triggers an inflammatory response.
Right: In FMF and with certain CDC42 variants, the interaction between pyrin and CDC42 becomes pathologically enhanced. Consequently, pyrin–CDC42 clusters form more readily even in the absence of invading pathogens, priming pyrin for activation by even minor stimuli and resulting in excessive inflammation.
Credit
Illustrator: Ivana Duic
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CC BY-NC-ND