| First Author | Liao Y | Year | 2023 |
| Journal | EMBO J | Volume | 42 |
| Issue | 1 | Pages | e110780 |
| PubMed ID | 36373462 | Mgi Jnum | J:332582 |
| Mgi Id | MGI:7427313 | Doi | 10.15252/embj.2022110780 |
| Citation | Liao Y, et al. (2023) The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1beta release via exosomes. EMBO J 42(1):e110780 |
| abstractText | IL-1beta 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-1beta-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-1beta complex to Tsg101, a component of the ESCRT complex, and enables the packaging of GSDMD and IL-1beta 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-1beta. |
