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The Journal of Lipid Research, Vol. 39, 821-833, April 1998
Copyright © 1998 by Lipid Research, Inc.

Original Article

The carboxy-terminal region of human lipoprotein lipase is necessary for its exit from the endoplasmic reticulum

Correspondence to: Senén Vilaró.

Certain missense substitutions on the human lipase (hLPL) gene produce mutated proteins that are retained in different compartments along the secretory pathway. The purpose of the present study was to elucidate whether the C-terminal domain of the hLPL molecule could be important for secretion. We constructed by site-directed mutagenesis three carboxy-terminal mutated (F ³⁸⁸Stop, K⁴²⁸Stop and K⁴⁴¹Stop) hLPL cDNAs that were expressed in COS1 cells. Immunoblotting of cell extracts showed that all three constructs led to similar levels of protein. Both wild type (WT) hLPL and the truncated K⁴⁴¹Stop hLPL were secreted to the extracellular medium, and presented a similar intracellular distribution pattern as shown by immunofluorescence. Neither F³⁸⁸Stop nor K⁴²⁸Stop hLPL protein was detected in cell medium. Immunofluorescence experiments showed that both truncated hLPL were retained within an intracellular compartment, which became larger. Double immunofluorescence analysis using antibodies against LPL and antiprotein disulfide isomerase as a marker showed that the truncated K⁴²⁸Stop hLPL was retained within the rough endoplasmic reticulum. This truncated protein was not found in other compartments in the secretory pathway, such as Golgi complex and lysosomes, indicating that it did not exit the endoplasmic reticulum. Further analysis of the C-terminal region of the LPL molecular model showed both that F ³⁸⁸Stop and K⁴²⁸Stop hLPL truncated proteins are highly hydrophobic.

As retention of secretory proteins in the rough endoplasmic reticulum is a quality control mechanism of the secretory pathway, we conclude that the C-terminal domain of hLPL is critical for correct intracellular processing of the newly synthesized protein.—Buscà, R., M. Martínez, E. Vilella, J. Peinado, J. L. Gelpi, S. Deeb, J. Auwerx, M. Reina, and S. Vilaró. The carboxy-terminal region of human lipoprotein lipase is necessary for its exit from the endoplasmic reticulum. J. Lipid Res. 1998. 39: 821–833.

Supplementary key words: lipoprotein lipase, endoplasmic reticulum, carboxy-terminal domain, secretion, intracellular processing, immunofluorescence, structure

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