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Membrane insertion of chromogranin B for granule maturation in regulated secretion

By Gaya P. Yadav, Haiyuan Wang, Joke Ouwendijk, Mani Annamalai, Stephen Cross, Qiaochu Wang, D. Walker Hagan, Clayton Mathews, Edward A. Phelps, Paul Verkade, Michael X. Zhu, Qiu-Xing Jiang

Posted 29 Dec 2019
bioRxiv DOI: 10.1101/2019.12.28.890053

Regulated secretion serves responses to specific stimuli in eukaryotes. An anion conductance was found essential for maturation and acidification of secretory granules four decades ago, but its genetic identity was unknown. We now demonstrate that chromogranin B (CHGB), an obligate granule protein, constitutes the long-sought anion channel. High-pressure freezing immuno-electron microscopy and biochemical assays showed native CHGB in close proximity to secretory granule membranes, and its membrane-bound and soluble forms both reconstituted Cl- channels. Release of secretory granules delivered CHGB clusters to plasma membranes, which dominate whole-cell anion conductance. Intragranular pH measurements and cargo maturation assays found that CHGB channels supported proinsulin - insulin conversion and dopamine-loading in neuroendocrine cells. β-cells from Chgb-/- mice exhibited significant granule deacidification, accounting for hyperproinsulinemia, altered glucose-tolerance response and lower dopamine concentration in chromaffin granules in these animals. Membrane insertion of well-conserved CHGB is thus indispensable for granule maturation in exocrine, endocrine and neuronal cells.

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