Protection from Endogenous Perforin: Glycans and the C Terminus Regulate Exocytic Trafficking in Cytotoxic Lymphocytes
Amelia J Brennan, Jenny Chia, Kylie A Browne, Annette Ciccone, Sarah Ellis, Jamie A Lopez, Olivia Susanto, Sandra Verschoor, Hideo Yagita, James C Whisstock, Joseph A Trapani, Ilia Voskoboinik
IMMUNITY | CELL PRESS | Published : 2011
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..View full abstract
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A.J.B. and J.A.L. are NHMRC Training Fellows, J.C. is a recipient of a CCV scholarship, J.C.W. is an ARC Federation Fellow and Honorary NHMRC Principal Research Fellow, J.A.T. was previously an NHMRC Senior Principal Research Fellow, and I.V. is an NHMRC Career Development Fellow. The authors greatly acknowledge the helpful comments of R.H.P. Law and D. Hoke, the technical assistance of the late K. Mitchelhill, and the NHMRC for grant support.