Granzyme B: a natural born killer

Immunol Rev. 2003 Jun;193:31-8. doi: 10.1034/j.1600-065x.2003.00044.x.

Abstract

A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL-mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose-6-phosphate/insulin-like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase-3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B-mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase-3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Caspases / immunology
  • Enzyme Activation / immunology
  • Granzymes
  • Humans
  • Serine Endopeptidases / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • Caspases