NINJURIN 1 ROLE IN CELL DEATH

The ninjurin family proteins are a group of double-transmembrane proteins that are ubiquitously expressed and evolutionary conserved from flies to humans. The Drosophila genome contains 3 members, NINJ-A, -B, and -C, while mammals contain two homologues, NINJ1 and NINJ2. NINJ1 is a 16kD protein, predicted to contain two transmembrane domains and two extracellular domains, the N- and C-terminus. It was initially reported to function as an cell-cell adhesion molecule, and previous studies have reported NINJ1 role in nerve regeneration after injury, inflammation, and tumour suppression field 9,10,11. It new role as an executor of PMR thus opens up a new study area. Specifically kayagaki et al. reported that NINJ1 controls post-cell death PMR in pyroptotic macrophages from mice. Here, NINJ1 deficiency blocked PMR and the release of large DAMPs. However, during pyroptosis NINJ1 acts downstream of GSDMD pore formation as the release of IL-1is not affected by NINJ1 deficiency. Importantly, NINJ1 also mediated PMR after toxin-induced cell permeabilization, during secondary necrosis and partially upon induction of necroptosis. It should be note that, the evolutionarily conserved alpha-helix within the N-terminus domain is required to induce cell lysis.

Therefore, NINJ1 has emerged as a common regulator of PMR downstream of many types of regulated cell death. However, this discovery has raised several questions, as the mechanistic insights into NINJ1 activation are still unknown. Moreover, its structure in resting cells and upon cell death induction remains elusive. There is evidence of NINJ1 oligomerization upon cell death activation, but it is still unclear whether those oligomers induce PMR directly or indirectly. Thus, the aims of my PhD project are to investigate the signals and mechanism that mediates NINJ1 activation, define the mechanism by which NINJ1 induces PMR and define the biological importance of NINJ1 in other pathways of cell death and host defense.