From pores to rupture: Structural basis and regulation of lytic cell death by gasdermins and NINJ1

Gasdermins (GSDMs) are a family of pore-forming proteins that execute lytic cell death by forming large β-barrel pores in cellular membranes. While traditionally regarded as the terminal effectors of pyroptosis, recent advances have revealed that GSDM pores alone are insufficient to cause full plasma membrane rupture, prompting the identification of nerve injury-induced protein 1 (Ninjurin 1 or NINJ1) as a critical executor of terminal cell lysis. This review provides an in-depth overview of the structural basis of GSDM pore formation and the regulatory mechanisms that govern their activity, including diverse post-translational modifications, such as ubiquitination, palmitoylation, and poly(ADP-ribosyl)ation. We also expand our discussion to the noncanonical activation strategies observed in bacterial, fungal, and ancient eukaryotic GSDM homologs. We further explore the molecular mechanisms for NINJ1 activation, highlighting its global role in mediating plasma membrane rupture downstream of multiple lytic cell death pathways. Finally, we discuss the pathological implications of dysregulated NINJ1 activity in related diseases, emphasizing its therapeutic potential as a universal modulator of terminal cell rupture.