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SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion

Chen, Xiao-Wei, Wang, He, Bajaj, Kanika, Zhang, Pengcheng, Meng, Zhuo-Xian, Ma, Danjun, Bai, Yongsheng, Liu, Hui-Hui, Adams, Elizabeth, Baines, Andrea, Yu, Genggeng, Sartor, Maureen A, Zhang, Bin, Yi, Zhengping, Lin, Jiandie, Young, Stephen G, Schekman, Randy, Ginsburg, David·2013·eLife
DOI 10.7554/elife.00444PMC PMC3622177
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Abstract

The secretory pathway of eukaryotic cells packages cargo proteins into COPII-coated vesicles for transport from the endoplasmic reticulum (ER) to the Golgi. We now report that complete genetic deficiency for the COPII component SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in COPII vesicle formation and cargo recruitment. However, these animals exhibit markedly reduced plasma cholesterol, with mutations in Apoe and Ldlr epistatic to Sec24a , suggesting a receptor-mediated lipoprotein clearance mechanism. Consistent with these data, hepatic LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER. Our findings also identify partial overlap in cargo selectivity between SEC24A and SEC24B, suggesting a previously unappreciated heterogeneity in the recruitment of secretory proteins to the COPII vesicles that extends to soluble as well as trans-membrane cargoes.

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Metadata

Authors
Chen, X.-W., Wang, H., Bajaj, K., Zhang, P., Meng, Z.-X., Ma, D., Bai, Y., Liu, H.-H., Adams, E., Baines, A., Yu, G., Sartor, M. A., Zhang, B., Yi, Z., Lin, J., Young, S. G., Schekman, R., & Ginsburg, D.
Affiliations
  • Life Sciences Institute, University of Michigan
  • Department of Molecular and Cell Biology, University of California, Berkeley
  • Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University
  • Department of Bioinformatics, University of Michigan
  • Department of Molecular Medicine, Cleveland Clinic
  • Program in Cell and Molecular Biology, University of Michigan
  • Department of Pharmaceutical Sciences, Wayne State University
  • Department of Medicine and Human Genetics, University of California, Los Angeles
  • Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley
  • Division of Molecular Medicine & Genetics, Howard Hughes Medical Institute, University of Michigan
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2013-04-09
Volume
2
ISSN
2050-084X
DOI
10.7554/elife.00444
PMC
PMC3622177
Cited by
115
References
4
Language
en
Update notices
correction (2026-06-24)
Licence
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (P01HL057346, R01HL039693)
  • American Heart Association (10POST4150049)

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