title: Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes.
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.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3002, Australia.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Brennan
authors.forename: Jenny
authors.initials: J
authors.lastname: Chia
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Browne
authors.forename: Annette
authors.initials: A
authors.lastname: Ciccone
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Lopez
authors.forename: Olivia
authors.initials: O
authors.lastname: Susanto
authors.forename: Sandra
authors.initials: S
authors.lastname: Verschoor
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Ilia
authors.initials: I
authors.lastname: Voskoboinik
mesh_terms: D000818:Animals; D001329:Autolysis / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement; D004721:Endoplasmic Reticulum / Q000276:immunology; D005089:Exocytosis; D006031:Glycosylation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D054353:Perforin / Q000172:deficiency / Q000276:immunology*; D011134:Polysaccharides / Q000276:immunology*; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D011134:Polysaccharides; D054353:Perforin