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Published online 17 April 2006. doi:10.1083/jcb.200506163
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 2, 241-251
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Article

Synaptotagmin IV is necessary for the maturation of secretory granules in PC12 cells



Malika Ahras, Grant P. Otto, and Sharon A. Tooze

Cancer Research UK, London Research Institute, London WC2A 3PX, England, UK

Correspondence to Sharon A. Tooze: sharon.tooze{at}cancer.org.uk

In neuroendocrine PC12 cells, immature secretory granules (ISGs) mature through homotypic fusion and membrane remodeling. We present evidence that the ISG-localized synaptotagmin IV (Syt IV) is involved in ISG maturation. Using an in vitro homotypic fusion assay, we show that the cytoplasmic domain (CD) of Syt IV, but not of Syt I, VII, or IX, inhibits ISG homotypic fusion. Moreover, Syt IV CD binds specifically to ISGs and not to mature secretory granules (MSGs), and Syt IV binds to syntaxin 6, a SNARE protein that is involved in ISG maturation. ISG homotypic fusion was inhibited in vivo by small interfering RNA–mediated depletion of Syt IV. Furthermore, the Syt IV CD, as well as Syt IV depletion, reduces secretogranin II (SgII) processing by prohormone convertase 2 (PC2). PC2 is found mostly in the proform, suggesting that activation of PC2 is also inhibited. Granule formation, and the sorting of SgII and PC2 from the trans-Golgi network into ISGs and MSGs, however, is not affected. We conclude that Syt IV is an essential component for secretory granule maturation.

Abbreviations used in this paper: BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; CD, cytoplasmic domain; HEK, human embryonic kidney; ISG, immature secretory granule; MSG, mature secretory granule; PC2, prohormone convertase 2; PNS, postnuclear supernatant; SgII, secretogranin II; Stx, syntaxin; Syt, synaptotagmin.


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