perforine

Perforin is a pore-forming cytolytic protein expressed by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. It is transported to the immune synapse in cytotoxic granules and released upon recognition of stressed or infected target cells. Perforin belongs to the membrane-attack complex/perforin (MACPF) superfamily and functions in concert with serine proteases called granzymes to eliminate target cells.

Mechanism and action

In a calcium-dependent process, perforin binds to the target cell membrane and polymerizes to create transmembrane pores. These pores facilitate the entry of granzymes into the cytoplasm, where they activate apoptotic pathways that lead to cell death. The perforin/granzyme axis is a central component of the immune system’s ability to remove virally infected or malignant cells while limiting collateral tissue damage.

Structure and regulation

Perforin is produced as a soluble monomer and, after release, oligomerizes on lipid membranes to form pores. It is a member of the MACPF/CDC family and contains domains that promote calcium-dependent membrane binding and pore formation. Proper regulation of perforin activity is essential to balance effective immune defense with the prevention of excessive tissue damage.

Clinical significance

Mutations in the PRF1 gene, which encodes perforin, can cause familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a severe pediatric immune disorder characterized by defective cytotoxic function and uncontrolled immune activation. Reduced perforin activity impairs clearance of infected or malignant cells and can contribute to hyperinflammatory syndromes, while dysregulated perforin expression has implications in various immune-related conditions.

Overall, perforin is a key effector protein in cytotoxic immune responses, enabling targeted cell death through pore-mediated delivery of granzymes.