Journal
EMBO JOURNAL
Volume 42, Issue 1, Pages -Publisher
WILEY
DOI: 10.15252/embj.2022110780
Keywords
ESCRT; exosome; GSDMD; inflammasome; IQGAP1
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This study reveals that IQGAP1 acts as an adaptor to promote the biogenesis of exosomes containing GSDMD and IL-1 beta after inflammasome activation. This process is dependent on the activation of CDC42 induced by LPS.
IL-1 beta 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-1 beta-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-1 beta complex to Tsg101, a component of the ESCRT complex, and enables the packaging of GSDMD and IL-1 beta 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-1 beta.
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