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First published online 11 April 2006
doi: 10.1242/jcs.02905

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Lumenal protein sorting to the constitutive secretory pathway of a regulated secretory cell

Roberto Lara-Lemus^1,*, Ming Liu^1,*, Mark D. Turner^2,*, Philipp Scherer³, Gudrun Stenbeck⁴, Puneeth Iyengar³ and Peter Arvan^1,

¹ Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
² Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Queen Mary's School of Medicine and Dentistry, University of London, Whitechapel, London, E1 1BB, UK
³ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
⁴ Bone and Mineral Centre, University College London, London, WC1E 6JJ, UK

Author for correspondence (e-mail: parvan{at}umich.edu)

Accepted 27 January 2006

Newly synthesized secretory granule content proteins are delivered via the Golgi complex for storage within mature granules, whereas constitutive secretory proteins are not stored. Most soluble proteins traveling anterograde through the trans-Golgi network are not excluded from entering immature secretory granules, whether or not they have granule-targeting signals. However, the `sorting-for-entry' hypothesis suggests that soluble lumenal proteins lacking signals enter transport intermediates for the constitutive secretory pathway. We aimed to investigate how these constitutive secretory proteins are sorted. In a pancreatic ß-cell line, we stably expressed two lumenal proteins whose normal sorting information has been deleted: alkaline phosphatase, truncated to eliminate its glycosylphosphatidylinositol membrane anchor (SEAP); and Cab45₃₆₁, a Golgi lumenal resident, truncated to eliminate its intracellular retention (Cab₃₀₈Myc). Both truncated proteins are efficiently secreted, but whereas SEAP enters secretory granules, Cab₃₀₈Myc behaves as a true constitutive marker excluded from granules. Interestingly, upon permeabilization of organelle membranes with saponin, SEAP is extracted as a soluble protein whereas Cab₃₀₈Myc remains associated with the membrane. These are among the first data to support a model in which association with the lumenal aspect of Golgi and/or post-Golgi membranes can serve as a means for selective sorting of constitutive secretory proteins.

Key words: Trans-Golgi network, Granule maturation, Constitutive-like secretory pathway

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