Protection from Endogenous Perforin: Glycans and the C Terminus Regulate Exocytic Trafficking in Cytotoxic Lymphocytes Academic Article uri icon

abstract

  • Cytotoxic lymphocyte-mediated apoptosis is dependent on the delivery of perforin to secretory granules and its ability to form calcium-dependent pores in the target cell after granule exocytosis. It is unclear how cytotoxic lymphocytes synthesize and store perforin without incurring damage or death. We discovered that the extreme C terminus of perforin was essential for rapid trafficking from the endoplasmic reticulum to the Golgi compartment. Substitution of the C-terminal tryptophan residue resulted in retention of perforin in the ER followed by calcium-dependent toxic activity that eliminated host cells. We also found that N-linked glycosylation of perforin was critical for transport from the Golgi to secretory granules. Overall, an intact C terminus and N-linked glycosylation provide accurate and efficient export of perforin from the endoplasmic reticulum to the secretory granules and are critical for cytotoxic lymphocyte survival.

authors

  • Brennan, Amelia J
  • Chia, Jenny
  • Browne, Kylie A
  • Ciccone, Annette
  • Ellis, Sarah
  • Lopez, Jamie A
  • Susanto, Olivia
  • Verschoor, Sandra
  • Yagita, Hideo
  • Whisstock, James C
  • Trapani, Joseph A
  • Voskoboinik, Ilia

publication date

  • June 2011