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First published online May 6, 2009
doi: 10.1242/10.1242/jcs.045625

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ATF6 induces XBP1-independent expansion of the endoplasmic reticulum

Hemamalini Bommiasamy^1,*,, Sung Hoon Back^2,*, Paolo Fagone³, Kyungho Lee^2,, Sasha Meshinchi⁴, Elizabeth Vink^5,, Rungtawan Sriburi^1,¶, Matthew Frank³, Suzanne Jackowski³, Randal J. Kaufman^2,5,6,** and Joseph W. Brewer^7,**

¹ Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
² Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
³ Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN 38105, USA
⁴ Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
⁵ Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
⁶ Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
⁷ Department of Microbiology and Immunology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA

^** Authors for correspondence (e-mails: kaufmanr{at}umich.edu; jbrewer{at}jaguar1.usouthal.edu)

Accepted 9 February 2009

A link exists between endoplasmic reticulum (ER) biogenesis and the unfolded protein response (UPR), a complex set of signaling mechanisms triggered by increased demands on the protein folding capacity of the ER. The UPR transcriptional activator X-box binding protein 1 (XBP1) regulates the expression of proteins that function throughout the secretory pathway and is necessary for development of an expansive ER network. We previously demonstrated that overexpression of XBP1(S), the active form of XBP1 generated by UPR-mediated splicing of Xbp1 mRNA, augments the activity of the cytidine diphosphocholine (CDP-choline) pathway for biosynthesis of phosphatidylcholine (PtdCho) and induces ER biogenesis. Another UPR transcriptional activator, activating transcription factor 6 (ATF6), primarily regulates expression of ER resident proteins involved in the maturation and degradation of ER client proteins. Here, we demonstrate that enforced expression of a constitutively active form of ATF6 drives ER expansion and can do so in the absence of XBP1(S). Overexpression of active ATF6 induces PtdCho biosynthesis and modulates the CDP-choline pathway differently than does enforced expression of XBP1(S). These data indicate that ATF6 and XBP1(S) have the ability to regulate lipid biosynthesis and ER expansion by mechanisms that are at least partially distinct. These studies reveal further complexity in the potential relationships between UPR pathways, lipid production and ER biogenesis.

Key words: Endoplasmic reticulum biogenesis, Unfolded protein response, ATF6, XBP1, Lipid biosynthesis

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