Phosphatidylinositol 4,5-bisphosphate: an emerging cell death mediator and immune regulator

Phan TK, Lay FT, Jarva M, Kvansakul M and Hulett MD

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University.

Phosphorylated phosphatidylinositol lipids, or phosphoinositides (PIPs), vitally regulate diverse cellular processes, including signalling transduction, cytoskeletal reorganisation, membrane dynamics and cellular trafficking. However, PIPs have been inadequately investigated in the context of cell death and inflammation, where they are mainly regarded as secondary messengers of PI3K-Akt signalling. Interestingly, recent studies implied their importance in mediating cell death by demonstrating that PIPs, particularly phosphatidylinositol 4,5-bisphosphate (PIP2), are essential effectors for different forms of programmed cell death. MLKL and gasdermin D require PIP binding to execute necroptosis and pyroptosis respectively. In our studies, we reported biphasic functions of PIP2 in mediating cytokine induction and necrotic cell death in response to low and high concentration of host defense peptides, particular human β-defensins (HBDs). Using multiple biochemical and cell biological approaches, we was able to show that the interaction of HBD-3 with PIP2 is important for receptor-independent PI3K-Akt-NF-κΒ-mediated cytokine induction at its sub-cytotoxic level. Higher concentration of HBD-3 also binds to PIP2, however leading to membrane blebbing and acute cell permeabilisation in mammalian cells. Furthermore, in our most recent study, it was found that PIP2, via a different mechanism, mediates pathogenic fungal cell killing by HBD-2, a closely-related defensin, by promoting a necrotic HBD-2:PIP2 oligomeric complex. Our findings highlight the critical roles of PIPs, particularly PIP2, in (i) orchestrating various cellular processes including a novel role in immune response and (ii) mediating cell death upon in different scenarios strategically targeting both host and pathogen cells.