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You had me at PELO: a “Ribosome Rescuer” induces NLR inflammasome assembly

Cellular & Molecular Immunology volume 21, pages 1–2 (2024)Cite this article

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Pyroptosis, an inflammatory form of programmed cell death, eliminates a niche where pathogens replicate, providing overall benefits to a host. When left uncontrolled, pyroptosis can lead to severe pathology. Overactive pyroptotic activation has been implicated in neuroinflammation, cardiovascular disease, acute respiratory distress syndrome (ARDS), and many other diseases [1,2,3]. Because of its multiple and permanent consequences, pyroptosis is a highly regulated signaling pathway. Major regulators of pyroptosis are NLR inflammasomes, which are activated by various “danger” signals such as ATP. Notably, high NLR levels are associated with cell death. Once assembled, this inflammasome promotes pyroptotic cell death by activating the pore-forming protein gasdermin D (GSDMD) protein. GSDMD oligomerizes, is inserted into the cell membrane, where it forms a pore, leading to lytic cell death and release of biologically active interleukin 1β (IL-1β). The activation of IL-1β and GSDMD depend on caspase 1, which is also activated after inflammasome assembly. Despite being a major regulatory mechanistic factor in pyroptotic cell death and release of biologically active IL-1β, the conformational changes required for inflammasome activation and assembly are poorly understood. In this regard, a recent study from Wu et al. shed some light on the requirements for NLR inflammasome assembly by introducing a previously unknown contributor to NLR inflammasome assembly [4].

Inflammasome-mediated pyroptotic cell death is essential to a robust immune response to many pathogens. For example, L. monocytogenes, an intracellular gram-positive pathogen, has been shown to activate many cytosolic NLR inflammasomes by using bacterial toxins that dissolve the phagosome, enabling pathogen entry into the intracellular space [5]. These toxins, together with bacterial flagellin, activate multiple NLR inflammasomes, inducing the cleavage of both GSDMD and pro-IL-1β into their active forms. Active GSDMD oligomerizes and is inserted into the host cell membrane, forming pores that release IL-1β and induce lytic cell death. S. typhimurium, a gram-negative intracellular pathogen, also activates NLR inflammasomes via the action of LPS, bacterial toxins, and flagellin [6]. Inducing pyroptotic death ensures the elimination of the niches where these pathogens replicate, trapping them in cellular debris and inducing an antibacterial inflammatory response. When pyroptotic death is inhibited, pathogens replicate easily, making them detrimental to a host.

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Authors and Affiliations

  1. Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, 136 Harrison Avenue, Boston, MA, 02111, USA

    Zoie Magri & Alexander Poltorak

  2. Department of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA

    Alexander Poltorak

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  1. Zoie Magri
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ZM and AP wrote the manuscript. AP designed and generated the figure.

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Correspondence to Alexander Poltorak.

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Magri, Z., Poltorak, A. You had me at PELO: a “Ribosome Rescuer” induces NLR inflammasome assembly. Cell Mol Immunol 21, 1–2 (2024). https://doi.org/10.1038/s41423-023-01059-0

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