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XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum.

Sriburi R, Jackowski S, Mori K, Brewer JW - J. Cell Biol. (2004)

Bottom Line: When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation.Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis.These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.

ABSTRACT
When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation. Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis. These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.

Show MeSH
A model for how XBP1 links the UPR to ER biogenesis. In response to increased demand on the protein folding capacity of the ER, UPR-mediated splicing of XBP1 mRNA yields the XBP1(S) transcriptional activator. We propose that XBP1(S) induces expression of unknown gene products that lead to an increase in CCT activity and a large increase in CPT activity, thereby augmenting synthesis of PtdCho. Increased production of PtdCho, the major phospholipid of the ER membrane, is critical for expansion of the ER compartment.
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fig5: A model for how XBP1 links the UPR to ER biogenesis. In response to increased demand on the protein folding capacity of the ER, UPR-mediated splicing of XBP1 mRNA yields the XBP1(S) transcriptional activator. We propose that XBP1(S) induces expression of unknown gene products that lead to an increase in CCT activity and a large increase in CPT activity, thereby augmenting synthesis of PtdCho. Increased production of PtdCho, the major phospholipid of the ER membrane, is critical for expansion of the ER compartment.

Mentions: There are three isoforms of CCT: α, β2, and β3. CCTα is ubiquitously expressed, whereas the β isoforms exhibit tissue-specific expression that is ∼10-fold lower compared with CCTα (Jackowski et al., 2004). Quantitative real-time RT-PCR revealed no change in transcript levels for any of the CCT isoforms in XBP1(S)-transduced cells (Fig. 4 A). Likewise, Northern blotting revealed no change in the steady-state levels of CPT1 and CEPT1 transcripts (Fig. 4 B). These data suggest that enforced expression of XBP1(S) leads to post-transcriptional and/or post-translational regulation of the CCTα and CPT1/CEPT1 enzymes, thereby augmenting their activities and increasing synthesis of PtdCho (Fig. 5).


XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum.

Sriburi R, Jackowski S, Mori K, Brewer JW - J. Cell Biol. (2004)

A model for how XBP1 links the UPR to ER biogenesis. In response to increased demand on the protein folding capacity of the ER, UPR-mediated splicing of XBP1 mRNA yields the XBP1(S) transcriptional activator. We propose that XBP1(S) induces expression of unknown gene products that lead to an increase in CCT activity and a large increase in CPT activity, thereby augmenting synthesis of PtdCho. Increased production of PtdCho, the major phospholipid of the ER membrane, is critical for expansion of the ER compartment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172532&req=5

fig5: A model for how XBP1 links the UPR to ER biogenesis. In response to increased demand on the protein folding capacity of the ER, UPR-mediated splicing of XBP1 mRNA yields the XBP1(S) transcriptional activator. We propose that XBP1(S) induces expression of unknown gene products that lead to an increase in CCT activity and a large increase in CPT activity, thereby augmenting synthesis of PtdCho. Increased production of PtdCho, the major phospholipid of the ER membrane, is critical for expansion of the ER compartment.
Mentions: There are three isoforms of CCT: α, β2, and β3. CCTα is ubiquitously expressed, whereas the β isoforms exhibit tissue-specific expression that is ∼10-fold lower compared with CCTα (Jackowski et al., 2004). Quantitative real-time RT-PCR revealed no change in transcript levels for any of the CCT isoforms in XBP1(S)-transduced cells (Fig. 4 A). Likewise, Northern blotting revealed no change in the steady-state levels of CPT1 and CEPT1 transcripts (Fig. 4 B). These data suggest that enforced expression of XBP1(S) leads to post-transcriptional and/or post-translational regulation of the CCTα and CPT1/CEPT1 enzymes, thereby augmenting their activities and increasing synthesis of PtdCho (Fig. 5).

Bottom Line: When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation.Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis.These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.

ABSTRACT
When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation. Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis. These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.

Show MeSH