title: SEC23B is required for the maintenance of murine professional secretory tissues.
abstract: In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition. Missense mutations in the human COPII paralogues SEC23A and SEC23B result in craniolenticulosutural dysplasia and congenital dyserythropoietic anemia type II, respectively. We now report that mice completely deficient for SEC23B are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues. In SEC23B-deficient embryonic pancreas, defects occur in exocrine and endocrine tissues shortly after differentiation. Pancreatic acini are completely devoid of zymogen granules, and the ER is severely distended. Similar ultrastructural alterations are also observed in salivary glands, but not in liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. Although maintenance of the secretory pathway should be required by all cells, our findings reveal a surprising tissue-specific dependence on SEC23B for the ER exit of highly abundant cargo, with high levels of SEC23B expression observed in professional secretory tissues. The disparate phenotypes in mouse and human could result from residual SEC23B function associated with the hypomorphic mutations observed in humans, or alternatively, might be explained by a species-specific shift in function between the closely related SEC23 paralogues.
authors: Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors: Jiayi
authors: J
authors: Tao
authors: Min
authors: M
authors: Zhu
authors: He
authors: H
authors: Wang
authors: Solomon
authors: S
authors: Afelik
authors: Matthew P
authors: MP
authors: Vasievich
authors: Xiao-Wei
authors: XW
authors: Chen
authors: Guojing
authors: G
authors: Zhu
authors: Jan
authors: J
authors: Jensen
authors: David
authors: D
authors: Ginsburg
authors: Bin
authors: B
authors: Zhang
mesh_terms: D000423:Alcian Blue; D000818:Animals; D000880:Anthraquinones; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D010179:Pancreas / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D055571:Secretory Pathway / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D033921:Vesicular Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D000880:Anthraquinones; C543353:SEC23B protein, human; C575519:SEC23B protein, mouse; D033921:Vesicular Transport Proteins; C010078:alizarin; D000423:Alcian Blue