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Lipid-dependent regulation of the unfolded protein response.

Volmer R, Ron D - Curr. Opin. Cell Biol. (2014)

Bottom Line: Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6.These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER.However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Institute of Metabolic Science, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom; Université de Toulouse, INP, ENVT, INRA, UMR 1225, IHAP, Toulouse, France. Electronic address: r.volmer@envt.fr.

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Mechanisms of lipid sensing by the UPR transducers. Perturbations of the ER lipid bilayer composition could impair the folding of ER proteins, thereby activating the full-length UPR transducers via their lumenal unfolded proteins sensing domain (left panel). However, mutant IRE1 and PERK lacking their lumenal domain (ΔLD mutants, right panel) are also activated by lipid perturbations in a process that requires ER membrane tethering via a TM domain [19••,20••]. Lipid-dependent activation of the ΔLD UPR transducers is independent of unfolded protein accumulation and likely proceeds by association of the TM domains in response to changes in the biophysical properties of the membrane. Dimerization of the effector domains of IRE1 and PERK (required for their allosteric activation) follows association of the TM domains. In the full-length proteins, stability of the activating effector-domain dimer would be further increased by the dimerization of the lumenal domain of IRE1 or PERK. Response of TM domains to changes in lipid composition of the ER membrane likely modulates a cooperative process involving the dimerization of both the effector and the lumenal domains.
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fig0005: Mechanisms of lipid sensing by the UPR transducers. Perturbations of the ER lipid bilayer composition could impair the folding of ER proteins, thereby activating the full-length UPR transducers via their lumenal unfolded proteins sensing domain (left panel). However, mutant IRE1 and PERK lacking their lumenal domain (ΔLD mutants, right panel) are also activated by lipid perturbations in a process that requires ER membrane tethering via a TM domain [19••,20••]. Lipid-dependent activation of the ΔLD UPR transducers is independent of unfolded protein accumulation and likely proceeds by association of the TM domains in response to changes in the biophysical properties of the membrane. Dimerization of the effector domains of IRE1 and PERK (required for their allosteric activation) follows association of the TM domains. In the full-length proteins, stability of the activating effector-domain dimer would be further increased by the dimerization of the lumenal domain of IRE1 or PERK. Response of TM domains to changes in lipid composition of the ER membrane likely modulates a cooperative process involving the dimerization of both the effector and the lumenal domains.

Mentions: Direct evidence that lipids may activate the UPR independently of their effects on unfolded protein burden in the lumen was provided by the observation that IRE1 and PERK lacking their lumenal unfolded protein stress-sensing domains were activated in yeast deprived of inositol [19••] or mammalian cells exposed to saturated fatty acid [20••]. Activation of the mutant IRE1 and PERK lacking their lumenal domain required ER membrane tethering via a TM domain [20••]. Furthermore, sensitivity to the lipid composition of the membrane bilayer was observed in a reconstituted system composed only of liposomes and a truncated PERK lacking its lumenal domain, but retaining the TM and cytosolic effector domains [20••]. Thus, perturbations of ER membrane lipids can directly activate IRE1 and PERK independently of unfolded proteins in a process that requires TM domain insertion into the ER lipid bilayer (Figure 1).


Lipid-dependent regulation of the unfolded protein response.

Volmer R, Ron D - Curr. Opin. Cell Biol. (2014)

Mechanisms of lipid sensing by the UPR transducers. Perturbations of the ER lipid bilayer composition could impair the folding of ER proteins, thereby activating the full-length UPR transducers via their lumenal unfolded proteins sensing domain (left panel). However, mutant IRE1 and PERK lacking their lumenal domain (ΔLD mutants, right panel) are also activated by lipid perturbations in a process that requires ER membrane tethering via a TM domain [19••,20••]. Lipid-dependent activation of the ΔLD UPR transducers is independent of unfolded protein accumulation and likely proceeds by association of the TM domains in response to changes in the biophysical properties of the membrane. Dimerization of the effector domains of IRE1 and PERK (required for their allosteric activation) follows association of the TM domains. In the full-length proteins, stability of the activating effector-domain dimer would be further increased by the dimerization of the lumenal domain of IRE1 or PERK. Response of TM domains to changes in lipid composition of the ER membrane likely modulates a cooperative process involving the dimerization of both the effector and the lumenal domains.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376399&req=5

fig0005: Mechanisms of lipid sensing by the UPR transducers. Perturbations of the ER lipid bilayer composition could impair the folding of ER proteins, thereby activating the full-length UPR transducers via their lumenal unfolded proteins sensing domain (left panel). However, mutant IRE1 and PERK lacking their lumenal domain (ΔLD mutants, right panel) are also activated by lipid perturbations in a process that requires ER membrane tethering via a TM domain [19••,20••]. Lipid-dependent activation of the ΔLD UPR transducers is independent of unfolded protein accumulation and likely proceeds by association of the TM domains in response to changes in the biophysical properties of the membrane. Dimerization of the effector domains of IRE1 and PERK (required for their allosteric activation) follows association of the TM domains. In the full-length proteins, stability of the activating effector-domain dimer would be further increased by the dimerization of the lumenal domain of IRE1 or PERK. Response of TM domains to changes in lipid composition of the ER membrane likely modulates a cooperative process involving the dimerization of both the effector and the lumenal domains.
Mentions: Direct evidence that lipids may activate the UPR independently of their effects on unfolded protein burden in the lumen was provided by the observation that IRE1 and PERK lacking their lumenal unfolded protein stress-sensing domains were activated in yeast deprived of inositol [19••] or mammalian cells exposed to saturated fatty acid [20••]. Activation of the mutant IRE1 and PERK lacking their lumenal domain required ER membrane tethering via a TM domain [20••]. Furthermore, sensitivity to the lipid composition of the membrane bilayer was observed in a reconstituted system composed only of liposomes and a truncated PERK lacking its lumenal domain, but retaining the TM and cytosolic effector domains [20••]. Thus, perturbations of ER membrane lipids can directly activate IRE1 and PERK independently of unfolded proteins in a process that requires TM domain insertion into the ER lipid bilayer (Figure 1).

Bottom Line: Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6.These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER.However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Institute of Metabolic Science, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom; Université de Toulouse, INP, ENVT, INRA, UMR 1225, IHAP, Toulouse, France. Electronic address: r.volmer@envt.fr.

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Related in: MedlinePlus