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Journal of Lipid Research, Vol. 45, 1826-1834, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

apoA-IV tagged with the ER retention signal KDEL perturbs the intracellular trafficking and secretion of apoB

James W. Gallagher^*, Richard B. Weinberg and Gregory S. Shelness^1,*

^* Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Department of Internal Medicine and Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157

¹ To whom correspondence should be addressed. e-mail: gshelnes{at}wfubmc.edu

To examine the role of apolipoprotein A-IV (apoA-IV) in the intracellular trafficking and secretion of apoB, COS cells were cotransfected with microsomal triglyceride transfer protein (MTP), apoB-41 (amino terminal 41% of apoB), and either native apoA-IV or apoA-IV modified with the carboxy-terminal endoplasmic reticulum (ER) retention signal, KDEL (apoA-IV-KDEL). As expected, apoA-IV-KDEL was inefficiently secreted relative to native apoA-IV. Coexpression of apoB-41 with apoA-IV-KDEL reduced the secretion of apoB-41 by 80%. The apoA-IV-KDEL effect was specific, as neither KDEL-modified forms of human serum albumin or apoA-I affected apoB-41 secretion. Similar results were observed in McA-RH7777 rat hepatoma cells, which express endogenous MTP. The full inhibitory effect of apoA-IV-KDEL on apoB secretion was observed only for forms of apoB containing a minimum of the amino-terminal 25% of the protein (apoB-25). However, apoA-IV-KDEL inhibited the secretion of both lipid-associated and lipid-poor forms of apoB-25. Dual-label immunofluorescence microscopy of cells transfected with native apoA-IV and apoB-25 revealed that both apolipoproteins were localized to the ER and Golgi, as expected. However, when apoA-IV-KDEL was cotransfected with apoB-25, both proteins localized primarily to the ER.

These data suggest that apoA-IV may physically interact with apoB in the secretory pathway, perhaps reflecting a role in modulating the process of triglyceride-rich lipoprotein assembly and secretion.

Abbreviations: apoA-IV, apolipoprotein A-IV; DSP, dithiobis(succinimidyl propionate); ER, endoplasmic reticulum; HSA, human serum albumin; MTP, microsomal triglyceride transfer protein

Supplementary key words lipoproteins • chylomicrons • lipid absorption • lipid transport • triglycerides • protein trafficking • apolipoprotein A-IV • apolipoprotein B • endoplasmic reticulum

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