Cytotoxic cell granule-mediated apoptosis: Perforin delivers granzyme b-serglycin complexes into target cells without plasma membrane pore formation

Sunil S. Metkar, Baikun Wang, Miguel Aguilar-Santelises, Srikumar M. Raja, Lars Uhlin-Hansen, Eckhard Podack, Joseph A. Trapani, Christopher J. Froelich

Research output: Contribution to journalArticle

199 Scopus citations

Abstract

The mechanism underlying perforin (PFN)-dependent delivery of apoptotic granzymes during cytotoxic cell granule-mediated death remains speculative. Granzyme B (GrB) and perforin were found to coexist as multimeric complexes with the proteoglycan serglycin (SG) in cytotoxic granules, and cytotoxic cells were observed to secrete exclusively macromolecular GrB-SG. Contrary to the view that PFN acts as a gateway for granzymes through the plasma membrane, monomeric PFN and, strikingly, PFN-SG complexes were shown to mediate cytosolic delivery of macromolecular GrB-SG without producing detectable plasma membrane pores. These results indicate that granule-mediated apoptosis represents a phenomenon whereby the target cell perceives granule contents as a multi meric complex consisting of SG, PFN, and granzymes, which are, respectively, the scaffold, translocator, and targeting/informational components of this modular delivery system.

Original languageEnglish (US)
Pages (from-to)417-428
Number of pages12
JournalImmunity
Volume16
Issue number3
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Metkar, S. S., Wang, B., Aguilar-Santelises, M., Raja, S. M., Uhlin-Hansen, L., Podack, E., Trapani, J. A., & Froelich, C. J. (2002). Cytotoxic cell granule-mediated apoptosis: Perforin delivers granzyme b-serglycin complexes into target cells without plasma membrane pore formation. Immunity, 16(3), 417-428. https://doi.org/10.1016/S1074-7613(02)00286-8