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© The Rockefeller University Press, 0021-9525/1998//359 $5.00
The Journal of Cell Biology, Volume 141, Number 2, , 1998 359-371

Articles

Mannose 6–Phosphate Receptors Are Sorted from Immature Secretory Granules via Adaptor Protein AP-1, Clathrin, and Syntaxin 6–positive Vesicles



Judith Klumperman*, Regina Kuliawat{ddagger}, Janice M. Griffith*, Hans J. Geuze*, and Peter Arvan{ddagger}

* Department of Cell Biology and Center for Electron Microscopy, University of Utrecht, School of Medicine, 3584CX Utrecht, The Netherlands; and {ddagger} Division of Endocrinology and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461

The occurrence of clathrin-coated buds on immature granules (IGs) of the regulated secretory pathway suggests that specific transmembrane proteins are sorted into these buds through interaction with cytosolic adaptor proteins. By quantitative immunoelectron microscopy of rat endocrine pancreatic β cells and exocrine parotid and pancreatic cells, we show for the first time that the mannose 6–phosphate receptors (MPRs) for lysosomal enzyme sorting colocalize with the AP-1 adaptor in clathrin-coated buds on IGs. Furthermore, the concentrations of both MPR and AP-1 decline by ~90% as the granules mature. Concomitantly, in exocrine secretory cells lysosomal proenzymes enter and then are sorted out of IGs, just as was previously observed in β cells (Kuliawat, R., J. Klumperman, T. Ludwig, and P. Arvan. 1997. J. Cell Biol. 137:595–608). The exit of MPRs in AP-1/clathrin-coated buds is selective, indicated by the fact that the membrane protein phogrin is not removed from maturing granules. We have also made the first observation of a soluble N-ethylmaleimide–sensitive factor attachment protein receptor, syntaxin 6, which has been implicated in clathrin-coated vesicle trafficking from the TGN to endosomes (Bock, J.B., J. Klumperman, S. Davanger, and R.H. Scheller. 1997. Mol. Biol. Cell. 8:1261–1271) that enters and then exits the regulated secretory pathway during granule maturation. Thus, we hypothesize that during secretory granule maturation, MPR–ligand complexes and syntaxin 6 are removed from IGs by AP-1/clathrin-coated vesicles, and then delivered to endosomes.

Abbreviations used in this paper: AP, adaptor protein; CCV, clathrin-coated vesicle; CD-MPR, cation-dependent MPR; CI-MPR, cation-independent MPR; CPE, carboxypeptidase E; IG, immature granule; M6P, mannose 6-phosphate; MPR, mannose 6–phosphate receptor; ProB, procathepsin B; SNARE, soluble N-ethylmaleimide–sensitive factor attachment protein receptor.

Address all correspondence to Judith Klumperman, Faculty of Medicine, Department of Cell Biology, University of Utrecht, AZU Rm. H02.314, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. Tel.: (31) 302-507-653. Fax: (31) 302-541-797. E-mail: j.klumperman{at}lab.azu.nl


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