Pro-hormone secretogranin II regulates dense core secretory granule biogenesis in catecholaminergic cells.
Processes underlying the formation of dense core secretory granules (DCGs) of neuroendocrine cells are poorly understood. Here, we present evidence that DCG biogenesis is dependent on the secretory protein secretogranin (Sg) II, a member of the granin family of pro-hormone cargo of DCGs in neuroendocrine cells. Depletion of SgII expression in PC12 cells leads to a decrease in both the number and size of DCGs and impairs DCG trafficking of other regulated hormones. Expression of SgII fusion proteins in a secretory-deficient PC12 variant rescues a regulated secretory pathway. SgII-containing dense core vesicles share morphological and physical properties with bona fide DCGs, are competent for regulated exocytosis, and maintain an acidic luminal pH through the V-type H(+)-translocating ATPase. The granulogenic activity of SgII requires a pH gradient along this secretory pathway. We conclude that SgII is a critical factor for the regulation of DCG biogenesis in neuroendocrine cells, mediating the formation of functional DCGs via its pH-dependent aggregation at the trans-Golgi network.
Courel
Maïté
M
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838. Electronic address: mcourel@univ-rouen.fr.
Soler-Jover
Alex
A
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838.
Rodriguez-Flores
Juan L
JL
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838.
Mahata
Sushil K
SK
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838; Veteran Affairs San Diego Healthcare System, San Diego, California 92093.
Elias
Salah
S
INSERM U982, University of Rouen, 76821 Mont-St.-Aignan Cedex, France.
Montero-Hadjadje
Maïté
M
INSERM U982, University of Rouen, 76821 Mont-St.-Aignan Cedex, France.
Anouar
Youssef
Y
INSERM U982, University of Rouen, 76821 Mont-St.-Aignan Cedex, France.
Giuly
Richard J
RJ
National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093.
O'Connor
Daniel T
DT
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838; Veteran Affairs San Diego Healthcare System, San Diego, California 92093. Electronic address: doconnor@ucsd.edu.
Taupenot
Laurent
L
Department of Medicine, University of California San Diego, La Jolla, California 92093-0838; Veteran Affairs San Diego Healthcare System, San Diego, California 92093. Electronic address: ltaupenot@gmail.com.
D000818:Animals; D019556:COS Cells; D002395:Catecholamines / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002837:Chromaffin Granules / Q000378:metabolism; D020868:Gene Silencing; D005822:Genetic Vectors; D006863:Hydrogen-Ion Concentration; D055099:Neuroendocrine Cells / Q000378:metabolism; D016716:PC12 Cells; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D053381:Secretogranin II / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*
D002395:Catecholamines; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D053381:Secretogranin II