Protein supersaturation powers innate immune signaling
Voices in Infection Biology
- Date: Oct 4, 2023
- Time: 04:00 PM (Local Time Germany)
- Speaker: Randal Halfmann
- Stowers Institute for Medical Research, Kansas City, MO
- Location: Max Planck Institute for Infection Biology and via Zoom
- Room: seminar room 1+2
- Host: Marcus Taylor
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The response of cells to existential threats such as virus invasion often involves semi-crystalline polymerization of certain signaling proteins, but the highly ordered nature of the polymers has no known function. We hypothesized that the function is kinetic in nature, emerging from the nucleation barrier to the underlying phase transition, rather than the material polymers themselves. We explored this idea using fluorescence microscopy and Distributed Amphifluoric FRET (DAmFRET) to characterize the phase behavior of all 109 members of the human death fold domain (DFD) superfamily, the largest group of putatively polymerizing modules in immune signaling. We found that a small subset of the DFDs polymerized in a nucleation-limited manner that created a binary switch in the cell-wide state of the protein. These were enriched for hubs and bottlenecks of the endogenous DFD protein-protein interaction network. These nucleation barriers were retained or enhanced in the corresponding full-length signalosome adaptor proteins. We demonstrate that one of these, ASC, is endogenously constitutively supersaturated, confirming that its nucleation barrier stores latent energy for on-demand inflammasome assembly. We then conducted a comprehensive screen to identify nucleating interactions between DFDs, revealing that the DFDs themselves govern signaling specificity downstream of nucleation. We also identified crosstalk between the cell death subroutines of pyroptosis and extrinsic apoptosis, and validated one such heterotypic nucleating interaction in vivo. Finally, we show that DFD supersaturability governs the (ir)reversibility of programmed cell death signaling. We speculate that the thermodynamically volatile condition of innate immunity represents an evolutionary trade-off that, on the one hand, enables extremely sensitive and decisive responses to pathogens, but on the other, imposes the eventuality of spontaneous inflammatory cell death that may contribute to age-associated inflammation.