Perforinin

Perforin is a cytolytic pore-forming protein produced by cytotoxic lymphocytes, principally CD8+ T cells and natural killer (NK) cells. It plays a central role in the granule-mediated cytotoxic pathway, enabling killer cells to destroy virus-infected or malignant target cells. In some texts the term perforinin appears as an alternative spelling.

The perforin gene, PRF1, encodes the perforin protein and is expressed primarily in cytotoxic lymphocytes. Perforin is stored in cytotoxic granules together with granzymes and other effector molecules and is released at the immunological synapse when a target cell is recognized. The protein is secreted in a calcium-dependent manner and interacts with target membranes to form transmembrane pores.

Mechanistically, perforin monomers assemble into pores within the target cell membrane. These pores permit granzymes to enter the cytosol, where they activate caspases and initiate apoptotic pathways, or trigger alternative cell death routes if perforin activity is high. This pore-forming activity is a hallmark of the MACPF/ perforin family of proteins, which share structural features that enable membrane disruption.

Structure and family: Perforin is a soluble, glycoprotein of about 65 kilodaltons in its monomeric form and belongs to the membrane-attack complex perforin (MACPF) superfamily. Pore size is sufficient to allow sizable proteins such as granzymes to access the target cell interior.

Clinical significance: Genetic mutations in PRF1 can cause familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a severe immune dysregulation characterized by impaired cytotoxic function and hyperinflammation. Perforin deficiency increases susceptibility to infections and can contribute to lymphoma risk due to defective immune surveillance. Therapeutic approaches focus on restoring cytotoxic function or managing hyperinflammatory episodes.