Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation.
Pyrin, encoded by the MEFV gene, is best known for its gain-of-function mutations causing familial Mediterranean fever (FMF), an autoinflammatory disease. Pyrin forms a caspase-1-activating inflammasome in response to inactivating modifications of Rho GTPases by various bacterial toxins or effectors. Pyrin-mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules, but its mechanism of activation is unknown. Here we show that Pyrin was phosphorylated in bone marrow-derived macrophages and dendritic cells. We identified Ser-205 and Ser-241 in mouse Pyrin whose phosphorylation resulted in inhibitory binding by cellular 14-3-3 proteins. The two serines underwent dephosphorylation upon toxin stimulation or bacterial infection, triggering 14-3-3 dissociation, which correlated with Pyrin inflammasome activation. We developed antibodies specific for phosphorylated Ser-205 and Ser-241, which confirmed the stimuli-induced dephosphorylation of endogenous Pyrin. Mutational analyses indicated that both phosphorylation and signal-induced dephosphorylation of Ser-205/241 are important for Pyrin activation. Moreover, microtubule drugs, including colchicine, commonly used to treat FMF, effectively blocked activation of the Pyrin inflammasome. These drugs did not affect Pyrin dephosphorylation and 14-3-3 dissociation but inhibited Pyrin-mediated apoptosis-associated Speck-like protein containing CARD (ASC) aggregation. Our study reveals that site-specific (de)phosphorylation and microtubule dynamics critically control Pyrin inflammasome activation, illustrating a fine and complex mechanism in cytosolic immunity.
['Gao|Wenqing|W|', 'Yang|Jieling|J|', 'Liu|Wang|W|', 'Wang|Yupeng|Y|', 'Shao|Feng|F|']
D048948:14-3-3 Proteins D000818:Animals D001427:Bacterial Toxins D004768:Enterotoxins D057809:HEK293 Cells D006801:Humans D058847:Inflammasomes D051379:Mice D008810:Mice, Inbred C57BL D008870:Microtubules D010766:Phosphorylation D000071198:Pyrin D050257:Tubulin Modulators
phosphorylation Pyrin inflammasome FMF Rho toxins