However, there are currently no tools to study the dynamics of large oligomeric pores spanning their activation, formation, and function in live cells. Unlike stably integrated membrane ion channels, gasdermin pores require activation and assembly. If true, such a mechanism would allow the cells to simply regulate and escape pyroptosis after activation, which would, in turn, constitute a new route to reversibly control these pores and hence the downstream inflammatory response. In this concept, biochemical signals can shut these pores after their formation and resume by opening on the short seconds/minutes time scale, thereby modulating the progression of pyroptosis. We hypothesized that pyroptotic pores can be halted. Specifically, it has not been explored whether gasdermin pores are dynamic. It is clear that these pores possess an outstanding property that dampens their lethality. Furthermore, the apparent immediate danger posed by these large pores is contrasted by their slow rate of nonspecific removal from the membrane 26. Large amounts of cytokines can be released from apparently intact and viable cells after gasdermin activation 24, 25. It is separable from cell death 20, can be overridden 21, and has been shown to collaborate with apoptotic signaling 22, 23. Yet unusual for a death program, pyroptosis is not always deadly. Consistent with this role in cell death, gasdermin knockout 14 and inhibition through irreversible protein modification 15, 16 prevented inflammation, and upregulation of pore formation in immune cells contributed to tumor suppression 17, 18, 19. Activated Gasdermin D (GSDMD) forms ~21 nm diameter oligomeric pores in the plasma membrane 2, 9, 10, 11, 12, causing osmotic imbalance, cell lysis, and driving the release of pro-inflammatory cytokines IL-1β and IL-18 13 to promote downstream T cell and macrophage activation responses. Canonical upstream activation of caspase-1 in humans and caspase-11 in mice triggers this lytic program via the cleavage of gasdermins 5, 6, 7, 8. It is also a root cause for inflammatory damage in tissues ranging from the endothelium 3 to cardiovascular tissues 4. The cell death program pyroptosis plays an important role in the development and homeostasis of multicellular organisms 1, 2.
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