A novel NINJ1-mediated regulatory step is essential for active membrane rupture and common to different cell death pathways

Abstract

Plasma membrane rupture (PMR), the final event in lytic cell death that is in part responsible for the release of pro-inflammatory signals, was believed to be a passive event that followed osmotic swelling. Kayagaki et al. ¹ have discovered that PMR is, in fact, mediated by ninjurin-1 (NINJ1), adding a novel regulatory step that is conserved across different types of lytic cell death, such as pyroptosis, necroptosis, and apoptosis. PMR is dependent on NINJ1 oligomerization, which is mediated by its highly conserved putative N-terminal α-helix. In vivo data suggest that the NINJ1-dependent secretome that is released upon PMR is likely to modulate antimicrobial host defense, suggesting this additional regulatory step also has physiological relevance.

Keywords: DAMPs; NINJ1; PCD; PMR; plasma membrane rupture.

Figure 1. Long-held (A) and proposed (B) models for pyroptosis- and post-apoptosis-related plasma membrane rupture (PMR)

Prior to Kayagaki et al., PMR in pyroptosis and post-apoptosis were considered passive events caused by the mechanical stress induced by osmotic swelling (A). In the proposed model (B), osmotic swelling does not drive PMR. Instead, ninjurin-1 (NINJ1)-mediated pores are formed that increases plasma membrane permeability, causing a rupture that not only releases cytosolic content, including lactate dehydrogenase (LDH), but also large danger-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1). Previously, these were thought to be co-released with pro-inflammatory cytokines. NINJ1, therefore, is a mediator of PMR and has pro-inflammatory roles.