Electrostatic influence on IL-1 transport through the GSDMD pore
Wen Jun Xie1, Shiyu Xia2,3, Arieh Warshel4
1Department of Chemistry, University of Southern California, Los Angeles, CA 90089.
Summary
Gasdermin D (GSDMD) pores release interleukin-1 (IL-1) from living cells. Membrane lipids and salt concentration modulate this release by altering the pore's electrostatic environment.
Area of Science:
- Cell Biology
- Biophysics
- Immunology
Background:
- Gasdermin D (GSDMD) forms pores in cell membranes, crucial for pyroptosis and releasing inflammatory cytokines like interleukin-1 (IL-1).
- GSDMD-mediated IL-1 release from living cells occurs independently of pyroptosis.
- Protein release through GSDMD pores is influenced by both cargo size and electrostatic interactions.
Purpose of the Study:
- To elucidate the mechanism of GSDMD pore function in channeling IL-1 release from living cells.
- To investigate the role of membrane lipids and salt concentration in regulating GSDMD-mediated IL-1 transport.
Main Methods:
- Computational modeling to determine the electrostatic requirements for IL-1 passage through GSDMD pores.
- Liposome leakage assays to experimentally validate predictions regarding salt's effect on GSDMD pore function.
Main Results:
- Computational analysis indicated that acidic membrane lipids are essential for neutralizing positive charges within the GSDMD pore to facilitate IL-1 release.
- Experimental validation confirmed that salt concentration attenuates the electrostatic filtering capacity of the GSDMD pore.
- A calibrated electrostatic screening factor was required to reconcile computational predictions with experimental observations, suggesting non-bulk ion distribution within the pore.
Conclusions:
- GSDMD pore function in IL-1 transport is critically dependent on electrostatic interactions.
- Membrane lipid composition and surrounding salt concentration are key extrinsic factors that modulate the GSDMD pore's electrostatic environment and IL-1 release.
- Further investigation into ion distribution within the GSDMD pore is warranted.
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