The C. elegans PAQR-2 and IGLR-2 membrane homeostasis proteins are uniquely essential for tolerating dietary saturated fats

Devkota, Ranjan; Henricsson, Marcus; Borén, Jan; Pilon, Marc

doi:10.1016/j.bbalip.2021.158883

Cited by 17 publications

(18 citation statements)

References 48 publications

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“…IGLR-2 is loosely homologous to mammalian LRIG proteins, a family with nearly 40 members [36], though a functional IGLR-2 ortholog has not yet been identified. Bifluorescence complementation (BiFC) and fluorescence resonance energy transfer (FRET) studies have shown that IGLR-2 localizes to the plasma membrane where it interacts in a membrane rigidity-dependent manner with PAQR-2 [28,37]. Additionally, structurefunction studies indicate that the two proteins interact via their transmembrane domains and, more speculatively, that IGLR-2 may help displace the cytoplasmic PAQR-2 domain to facilitate access of substrates to the active site [26,37].…”

Section: Lessons From C Elegansmentioning

confidence: 99%

“…Bifluorescence complementation (BiFC) and fluorescence resonance energy transfer (FRET) studies have shown that IGLR-2 localizes to the plasma membrane where it interacts in a membrane rigidity-dependent manner with PAQR-2 [28,37]. Additionally, structurefunction studies indicate that the two proteins interact via their transmembrane domains and, more speculatively, that IGLR-2 may help displace the cytoplasmic PAQR-2 domain to facilitate access of substrates to the active site [26,37]. Note also that IGLR-2 is not required for PAQR-1 function, suggesting that PAQR-1 either has a basal constitutive activity or is regulated via a separate mechanism [26].…”

Section: Lessons From C Elegansmentioning

confidence: 99%

“…Remarkably, an unbiased genetic screen to identify mutants intolerant of dietary palmitic acid (a C16:0 SFA) showed that PAQR-2 and IGLR-2 are the only two C. elegans proteins specifically essential to prevent lethal membrane rigidification by SFA-rich diets [37]. Additionally, screens for secondary mutations that compensate for the lack of PAQR-2 revealed the existence of two independent downstream branches in the PAQR-2/IGLR-2 pathway: "Branch 1" acts by upregulating the expression of desaturases, and its function can be replaced by gain-of-function alleles of NHR-49 (a homolog of the mammalian PPARs), MDT-15 (a homolog of the mammalian mediator subunit MED15) or SBP-1 (a homolog of the mammalian SREBPs) [29]; "Branch 2" acts by promoting PUFA production and/or their incorporation into phospholipids, and its function can be replaced by loss-of-function mutations in FLD-1 (a homolog of the mammalian TLCD1 and TLCD2 proteins) or ACS-13 (a homolog of the mammalian ACSL1) [32,33].…”

Section: Lessons From C Elegansmentioning

confidence: 99%

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Paradigm shift: the primary function of the “Adiponectin Receptors” is to regulate cell membrane composition

Pilon

2021

Lipids Health Dis

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The ADIPOR1 and ADIPOR2 proteins (ADIPORs) are generally considered as adiponectin receptors with anti-diabetic properties. However, studies on the yeast and C. elegans homologs of the mammalian ADIPORs, and of the ADIPORs themselves in various mammalian cell models, support an updated/different view. Based on findings in these experimental models, the ADIPORs are now emerging as evolutionarily conserved regulators of membrane homeostasis that do not require adiponectin to act as membrane fluidity sensors and regulate phospholipid composition. More specifically, membrane rigidification activates ADIPOR signaling to promote fatty acid desaturation and incorporation of polyunsaturated fatty acids into membrane phospholipids until fluidity is restored. The present review summarizes the evidence supporting this new view of the ADIPORs, and briefly examines physiological consequences.

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Section: Lessons From C Elegansmentioning

confidence: 99%

Section: Lessons From C Elegansmentioning

confidence: 99%

Section: Lessons From C Elegansmentioning

confidence: 99%

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Paradigm shift: the primary function of the “Adiponectin Receptors” is to regulate cell membrane composition

Pilon

2021

Lipids Health Dis

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“…Perturbations in membrane composition and properties can have dramatic consequences for the cell/organism. For instance, lipotoxicity can often be explained by excessive membranelipid packing that in turn can be caused by a diet rich in saturated fats or by the loss of membrane regulators such as the Adiponectin Receptors (AdipoR1 and AdipoR2) (Devkota et al, 2021a;Piccolis et al, 2019;Ruiz et al, 2021;Zhu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Ruiz

Devkota

Panagaki

et al. 2021

Preprint

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Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using unbiased lipidomics and proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism maintain membrane homeostasis and adapt to a variable environment.

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“…Perturbations in membrane composition and properties can have dramatic consequences for the cell/organism. For instance, lipotoxicity can often be explained by excessive membrane-lipid packing that in turn can be caused by a diet rich in saturated fats or by the loss of membrane regulators such as the Adiponectin Receptors (AdipoR1 and AdipoR2) [2][3][4][5] .…”

mentioning

confidence: 99%

Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis

et al. 2022

Self Cite

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Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organisms achieve membrane homeostasis and adapt to a variable environment.

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The C. elegans PAQR-2 and IGLR-2 membrane homeostasis proteins are uniquely essential for tolerating dietary saturated fats

Cited by 17 publications

References 48 publications

Paradigm shift: the primary function of the “Adiponectin Receptors” is to regulate cell membrane composition

Paradigm shift: the primary function of the “Adiponectin Receptors” is to regulate cell membrane composition

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis

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