Submitted on February 12, 2008
Revised on April 9, 2008
Accepted on May 27, 2008
Expression of CETP and splice variants induce same level of ER stress despite secretion efficiency differences
Maruja E. Lira, A. Katrina Loomis, Sara A. Paciga, David B. Lloyd, and John F. Thompson
Genomic Research, Helicos Biosciences, Cambridge, MA 02139
Corresponding Author: jthompson{at}helicosbio.com
The Cholesteryl Ester Transfer Protein (CETP) gene has been associated with a variety of phenotypes including HDL-C levels and more sporadically with cardiovascular disease, obesity, and extreme longevity. Alterations of CETP activity levels can be caused by single base polymorphisms as well as by alternative splicing. In addition to the previously characterized alternative splicing that skips exon 9, we found additional minor variants and characterized the activity of the resultant proteins. The novel variants skipped exon 9 sequences and inserted one of two in-frame exons from Alu-derived intronic sequences. None of the alternatively spliced variants is efficiently secreted and co-expression of them inhibits wild-type CETP secretion. Expression of the alternative spliced variants causes an induction of genes linked to the Endoplasmic Reticulum (ER) stress response including the neighboring HERPUD1 (Homocysteine- and Endoplasmic Reticulum Stress-Inducible Protein, Ubiquitin-Like Domain-Containing) gene. Unexpectedly, even though wild-type CETP is secreted much more efficiently than spliced variants, it induces the same degree of stress response as spliced variants while a control secreted protein does not. Conclusions: CETP plays a complex role in modulating ER stress with its expression inducing the response and its cholesteryl ester transfer activity and differential splicing modulating the response in other ways.
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