ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum.
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 6alpha (ATF6alpha), 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 ATF6alpha drives ER expansion and can do so in the absence of XBP1(S). Overexpression of active ATF6alpha induces PtdCho biosynthesis and modulates the CDP-choline pathway differently than does enforced expression of XBP1(S). These data indicate that ATF6alpha 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.
Bommiasamy
Hemamalini
H
Department of Microbiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Back
Sung Hoon
SH
Fagone
Paolo
P
Lee
Kyungho
K
Meshinchi
Sasha
S
Vink
Elizabeth
E
Sriburi
Rungtawan
R
Frank
Matthew
M
Jackowski
Suzanne
S
Kaufman
Randal J
RJ
Brewer
Joseph W
JW
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D046529:Microscopy, Electron, Transmission; D041681:NIH 3T3 Cells; D010713:Phosphatidylcholines / Q000096:biosynthesis; D017510:Protein Folding; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D000071717:X-Box Binding Protein 1
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D010713:Phosphatidylcholines; D011993:Recombinant Fusion Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D003566:Cytidine Diphosphate Choline