Slp1 and Slp2-a localize to the plasma membrane of CTL and contribute to secretion from the immunological synapse

Oliver Holt, Eiko Kanno, Giovanna Bossi, Sarah Booth, Tiziana Daniele, Alessandra Santoro, Maurizio Arico, Chika Saegusa, Mitsunori Fukuda, Gillian M. Griffiths

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Rab27a is required for polarized secretion of lysosomes from cytotoxic T lymphocytes (CTLs) at the immunological synapse. A series of Rab27a-interacting proteins have been identified; however, only Munc13-4 has been found to be expressed in CTL. In this study, we screened for expression of the synaptotagmin-like proteins (Slps): Slp1/JFC1, Slp2-a/ exophilin4, Slp3-a, Slp4/granuphilin, Slp5 and rabphilin in CTL. We found that both Slp1 and Slp2-a are expressed in CTL. Isoforms of Slp2-a in CTL showed variation of the linker region but conserved the C2A and C2B and Slp homology (SHD) domains. Both Slp1 and Slp2-a interact with Rab27a in CTL, and Slp2-a, but not Slp1, is rapidly degraded when Rab27a is absent. Slp2-a contains PEST-like sequences within its linker region, which render it susceptible to degradation. Both Slp1 and Slp2-a localize predominantly to the plasma membrane of both human and mouse CTLs, and we show that Slp2-a can focus tightly at the immunological synapse formed with a target cell. Individual knockouts of either Slp2-a or Slp1 fail to impair CTL-mediated killing of targets; however, overexpression of a dominant-negative construct consisting of the SHD of Slp2-a, which is 56% identical to that of Slp1, reduces target cell death, suggesting that both Slp1 and Slp2-a contribute to secretory lysosome exocytosis from CTL. These results suggest that both Slp1 and Slp2-a may form part of a docking complex, capturing secretory lysosomes at the immunological synapse.

Original languageEnglish
Pages (from-to)446-457
Number of pages12
JournalTraffic
Volume9
Issue number4
DOIs
Publication statusPublished - 2008 Apr 1

Keywords

  • CTL
  • Immunological synapse
  • Rab27a
  • Secretory lysosome
  • Slp2-a

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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