CRM1 mediates ASC nuclear export and inflammasome activation

Inflammasomes are multiprotein complexes of the innate immune system that sense different pathogens or danger signals, and have been implicated in the pathogenesis of multiple human inflammatory diseases. The translocation of adaptor protein ASC from the nucleus to the cytosol is important for inflammasome assembly and activation, but the mechanism remains unclear. Here we show that pharmacological inhibition or genetic deletion of chromosome region maintenance 1 (CRM1) in macrophages significantly inhibits the activation of NLRP3, AIM2, NLRC4 and pyrin inflammasomes. Mechanistically, CRM1 directly binds to the PYD domain of ASC to promote its nuclear-cytosolic transport. More importantly, treatment with CRM1 inhibitor KPT-330 or deletion of CRM1 in myeloid cells attenuates the pathological symptoms of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our findings reveal that CRM1 is an essential mediator for ASC nuclear export to promote inflammasome assembly and activation, which provides a potential target for inflammasome-related diseases.