The Ras GTPase‐activating‐like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL‐1β release via exosomes.

IL‐1β can exit the cytosol as an exosomal cargo following inflammasome activation in intestinal epithelial cells (IECs) in a Gasdermin D (GSDMD)‐dependent manner. The mechanistic connection linking inflammasome activation and the biogenesis of exosomes has so far remained largely elusive. Here, we report the Ras GTPase‐activating‐like protein IQGAP1 functions as an adaptor, bridging GSDMD to the endosomal sorting complexes required for transport (ESCRT) machinery to promote the biogenesis of pro‐IL‐1β‐containing exosomes in response to NLPR3 inflammasome activation. We identified IQGAP1 as a GSDMD‐interacting protein through a non‐biased proteomic analysis. Functional investigation indicated the IQGAP1‐GSDMD interaction is required for LPS and ATP‐induced exosome release. Further analysis revealed that IQGAP1 serves as an adaptor which bridges GSDMD and associated IL‐1β complex to Tsg101, a component of the ESCRT complex, and enables the packaging of GSDMD and IL‐1β into exosomes. Importantly, this process is dependent on an LPS‐induced increase in GTP‐bound CDC42, a small GTPase known to activate IQGAP1. Taken together, this study reveals IQGAP1 as a link between inflammasome activation and GSDMD‐dependent, ESCRT‐mediated exosomal release of IL‐1β. Synopsis: Exosomal release is one of the secretory routes for IL‐1β, however the mechanistic connection linking inflammasome activation and the biogenesis of exosomes remains unknown. This study identifies IQGAP1 as a link between inflammasome activation and GSDMD‐dependent, ESCRT‐mediated exosomal release of IL‐1β. Ras GTPase‐activating‐like protein IQGAP1 functions as an adaptor bridging GSDMD and associated IL‐1β complex to Tsg101 and enables its packaging into exosomes.IQGAP1‐GSDMD interaction is required for LPS and ATP‐induced exosome release.This process depends on an LPS‐induced increase in GTP‐bound CDC42, a small GTPase activating IQGAP1. [ABSTRACT FROM AUTHOR]