Disrupting membranes, controlling cell fate: the role of pore-forming proteins in cell death and therapy

Pore-forming proteins (PFPs), characterized by their ability to form pores or disrupt membranes are now recognized as key executioners of cell death, either as effectors of the immune system (non-cell-autonomous function), or of regulated cell death programs (cell autonomous function). To perforate membranes, most PFPs transition from water-soluble monomers or oligomers into multimeric and often supramolecular complexes, a process achieved via substantial structural transition of the PFP. Although they share the general ability to perforate cellular or intracellular membranes, PFPs differ in their membrane-binding preferences, the structural and functional characteristics of the pores they form (such as pore size, pore structure and ability to trigger membrane rupture) and the cell death mechanism they induce or execute. Herein, we review the specific traits of all key human PFPs, including their membrane specificity, regulation of their activity and the structure of the membrane pores they form, followed by insights into the therapeutic potential of PFPs and harnessing their abilities for cancer therapy.