Synaptotagmin VII Regulates Ca2+-Dependent Exocytosis of Lysosomes in Fibroblasts

doi:10.1083/jcb.148.6.1141

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© The Rockefeller University Press, 0021-9525/2000//1141 $5.00
The Journal of Cell Biology, Volume 148, Number 6, , 2000 1141-1150

Brief Report

Synaptotagmin VII Regulates Ca²⁺-Dependent Exocytosis of Lysosomes in Fibroblasts

Iñigo Martinez^a, Sabyasachi Chakrabarti^a, Turid Hellevik^b, Jennifer Morehead^a, Kimberly Fowler^a, and Norma W. Andrews^a^,b

^a Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06520
^b Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520
Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536.(203) 737-2630(203) 737-2410

Synaptotagmins (Syts) are transmembrane proteins with two Ca²⁺-bindingC₂ domains in their cytosolic region. Syt I, the most widelystudied isoform, has been proposed to function as a Ca²⁺ sensorin synaptic vesicle exocytosis. Several of the twelve knownSyts are expressed primarily in brain, while a few are ubiquitous(Sudhof, T.C., and J. Rizo. 1996. Neuron. 17: 379–388;Butz, S., R. Fernandez-Chacon, F. Schmitz, R. Jahn, and T.C.Sudhof. 1999. J. Biol. Chem. 274:18290–18296). The ubiquitouslyexpressed Syt VII binds syntaxin at free Ca²⁺ concentrations([Ca²⁺]) below 10 µM, whereas other isoforms require 200–500µM [Ca²⁺] or show no Ca²⁺-dependent syntaxin binding (Li,C., B. Ullrich, Z. Zhang, R.G.W. Anderson, N. Brose, and T.C.Sudhof. 1995. Nature. 375:594–599). We investigated theinvolvement of Syt VII in the exocytosis of lysosomes, whichis triggered in several cell types at 1–5 µM [Ca²⁺](Rodríguez, A., P. Webster, J. Ortego, and N.W. Andrews.1997. J. Cell Biol. 137:93–104). Here, we show that SytVII is localized on dense lysosomes in normal rat kidney (NRK)fibroblasts, and that GFP-tagged Syt VII is targeted to lysosomesafter transfection. Recombinant fragments containing the C₂Adomain of Syt VII inhibit Ca²⁺-triggered secretion of β-hexosaminidaseand surface translocation of Lgp120, whereas the C₂A domainof the neuronal- specific isoform, Syt I, has no effect. Antibodiesagainst the Syt VII C₂A domain are also inhibitory in both assays,indicating that Syt VII plays a key role in the regulation ofCa²⁺-dependent lysosome exocytosis.

Key Words: calcium-regulated • calcium sensor • lysosome • secretion • β-hexosaminidase

Abbreviations used in this paper: [Ca²⁺], free calcium concentration;GFP, green fluorescent protein; NRK, normal rat kidney; PFA,paraformaldehyde; SLO, streptolysin O; Syt, synaptotagmin.

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