Perforoinnin

Perforin, referred to here as perforoinnin in Finnish, is a pore-forming protein used by cytotoxic T lymphocytes and natural killer cells to eliminate infected or malignant cells. It is a member of the membrane attack complex/perforin (MACPF) superfamily and is encoded by the PRF1 gene in humans. Perforin is stored in the cytotoxic granules of immune cells and released during target cell recognition.

Mechanism and role in immunity: When a cytotoxic lymphocyte engages a target cell, perforin and granzymes are released into the immunological synapse via granule exocytosis. Perforin binds to the target cell membrane in a calcium-dependent manner and assembles into transmembrane pores. These pores permit granzymes to enter the target cell cytoplasm, where they activate caspases and other proteolytic pathways to drive apoptosis. At high concentrations, perforin can also cause direct lysis of the target cell. This pore-forming activity is essential for efficient delivery of cytotoxic enzymes and for controlling infections and tumor cells.

Structure and regulation: Perforin is synthesized as a precursor polypeptide that is processed into mature, active forms capable of forming pores. The pores created by perforin are typically nanometer-scale channels that disrupt membrane integrity and cellular homeostasis, enabling enzymatic entry into the cell.

Clinical significance: Defects in perforin production or function result in impaired cytotoxicity and are linked to familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a severe immune dysregulation. Alterations in perforin can influence susceptibility to infections and cancer, and studying its function informs understanding of immune responses and potential therapies.