Journal
JOURNAL OF LIPID RESEARCH
Volume 52, Issue 10, Pages 1775-1786Publisher
ELSEVIER
DOI: 10.1194/jlr.M017277
Keywords
endoplasmic reticulum; lipoprotein; secretion; Mia3; Tango1; Ctage5
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Funding
- [UL1 RR025774]
- [R01 DK079925]
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Through forward genetic screening in the mouse, a recessive mutation (couch potato, cpto) has been discovered that dramatically reduces plasma cholesterol levels across all lipoprotein classes. The cpto mutation altered a highly conserved residue in the Src homology domain 3 (SH3) domain of the Mia2 protein. Full-length hepatic Mia2 structurally and functionally resembled the related Mia3 protein. Mia2 localized to endoplasmic reticulum (ER) exit sites, suggesting a role in guiding proteins from the ER to the Golgi. Similarly to the Mia3 protein, Mia2's cytosolic C terminus interacted directly with COPII proteins Sec23 and Sec24, whereas its lumenal SH3 domain may facilitate interactions with secretory cargo. Fractionation of plasma revealed that Mia2(cpto/cpto) mice had lower circulating VLDL, LDL, HDL, and triglycerides. Mia2 is thus a novel, hepatic, ER-to-Golgi trafficking protein that regulates cholesterol metabolism.-Pitman, J. L., D. J. Bonnet, L. K. Curtiss, and N. Gekakis. Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites. J. Lipid Res. 2011. 52: 1775-1786.
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