Protection from endogenous perforin: Glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes

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

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)879 - 892
Number of pages14
JournalImmunity
Volume34
Issue number6
DOIs
Publication statusPublished - 2011

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