Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response

Micoogullari, Yagmur; Basu, Sankha S.; Ang, Jessie; Weisshaar, Nina; Schmitt, N.; Abdelmoula, Walid M.; Lopez, Begoña G.C.; Agar, Jeffrey N.; Agar, Nathalie Y.R.; Hanna, John

doi:10.1091/mbc.e19-07-0392

Cited by 22 publications

(20 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between ER stress and lipid metabolism is bidirectional: ER stress regulates lipid metabolism, and lipids can induce ER stress. An overabundance of SFAs induces ER stress, which can be mollified by PUFAs (41)(42)(43)(44). It is possible that HCMVinfected cells maintain a balance between PUFAs and SFA/MUFAs to limit lipotoxic stress.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids

Lindenmayer²,

Kline

et al. 2021

mBio

View full text Add to dashboard Cite

Stress and virus infection regulate lipid metabolism. Human cytomegalovirus (HCMV) infection induces fatty acid (FA) elongation and increases the abundance of lipids with very-long-chain FA (VLCFA) tails. While reprogramming of metabolism can be stress related, the role of stress in HCMV reprogramming of lipid metabolism is poorly understood. In this study, we engineered cells to knock out protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in the ER stress pathway and measured lipid changes using lipidomics to determine if PERK is needed for lipid changes associated with HCMV infection. In HCMV-infected cells, PERK promotes increases in the levels of phospholipids with saturated FA (SFA) and monounsaturated FA (MUFA) VLCFA tails. Further, PERK enhances FA elongase 7 (ELOVL7) protein levels, which elongates SFA and MUFA VLCFAs. Additionally, we found that increases in the elongation of polyunsaturated fatty acids (PUFAs) associated with HCMV infection were independent of PERK and that lipids with PUFA tails accumulated in HCMV-infected PERK knockout cells. Additionally, the protein levels of ELOVL5, which elongates PUFAs, are increased by HCMV infection through a PERK-independent mechanism. These observations show that PERK differentially regulates ELOVL7 and ELOVL5, creating a balance between the synthesis of lipids with SFA/MUFA tails and PUFA tails. Additionally, we found that PERK was necessary for virus replication and the infectivity of released viral progeny. Overall, our findings indicate that PERK—and, more broadly, ER stress—may be necessary for the membrane biogenesis needed to generate infectious HCMV virions. IMPORTANCE HCMV is a common herpesvirus that establishes lifelong persistent infections. While infection is asymptomatic in most people, HCMV causes life-threatening illnesses in immunocompromised people, including transplant recipients and cancer patients. Additionally, HCMV infection is a leading cause of congenital disabilities. HCMV replication relies on lipid synthesis. Here, we demonstrated that the ER stress mediator PERK controls FA elongation and the cellular abundance of several types of lipids following HCMV infection. Specifically, PERK promotes FA elongase 7 synthesis and phospholipids with saturated/monounsaturated very-long-chain FA tails. Overall, our study shows that PERK is an essential host factor that supports HCMV replication and promotes lipidome changes caused by HCMV infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids

Lindenmayer²,

Kline

et al. 2021

mBio

View full text Add to dashboard Cite

show abstract

“…Perhaps defective synthesis of long-chain FAs and/or sphingolipids, both of which have been linked to UPR-ER regulation [ 157 ], is the culprit. Indeed, very-long-chain FAs (>20C) can increase membrane saturation [ 158 ], which activates the UPR-ER LBS [ 71 ]. Targeted lipidomics in let-767-depleted worms would be a powerful approach to quantify changes in different very-long-chain FA levels in sphingolipids, possibly after ER membrane extraction [ 159 ].…”

Section: Potential -Omics Work Characterizing Upr-er Inducing Metmentioning

confidence: 99%

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Taubert

2021

Metabolites

View full text Add to dashboard Cite

Biological membranes are not only essential barriers that separate cellular and subcellular structures, but also perform other critical functions such as the initiation and propagation of intra- and intercellular signals. Each membrane-delineated organelle has a tightly regulated and custom-made membrane lipid composition that is critical for its normal function. The endoplasmic reticulum (ER) consists of a dynamic membrane network that is required for the synthesis and modification of proteins and lipids. The accumulation of unfolded proteins in the ER lumen activates an adaptive stress response known as the unfolded protein response (UPR-ER). Interestingly, recent findings show that lipid perturbation is also a direct activator of the UPR-ER, independent of protein misfolding. Here, we review proteostasis-independent UPR-ER activation in the genetically tractable model organism Caenorhabditis elegans. We review the current knowledge on the membrane lipid composition of the ER, its impact on organelle function and UPR-ER activation, and its potential role in human metabolic diseases. Further, we summarize the bi-directional interplay between lipid metabolism and the UPR-ER. We discuss recent progress identifying the different respective mechanisms by which disturbed proteostasis and lipid bilayer stress activate the UPR-ER. Finally, we consider how genetic and metabolic disturbances may disrupt ER homeostasis and activate the UPR and discuss how using -omics-type analyses will lead to more comprehensive insights into these processes.

show abstract

“…Variations in their properties have an impact on the membrane characteristics. This class of lipids is unevenly distributed between the different membranes in the cell [ 24 , 47 – 49 ]. By contrast, in photosynthetic membranes of plants the major constituents are the nonphosphorus galactolipids divided mainly into two classes, monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG).…”

Section: Classification and Composition Of Lipids In Plantsmentioning

confidence: 99%

Lipids Composition in Plant Membranes

Reszczyńska

Hanaka

2020

Cell Biochem Biophys

100

View full text Add to dashboard Cite

The paper focuses on the selected plant lipid issues. Classification, nomenclature, and abundance of fatty acids was discussed. Then, classification, composition, role, and organization of lipids were displayed. The involvement of lipids in xantophyll cycle and glycerolipids synthesis (as the most abundant of all lipid classes) were also discussed. Moreover, in order to better understand the biomembranes remodeling, the model (artificial) membranes, mimicking the naturally occurring membranes are employed and the survey on their composition and application in different kind of research was performed. High level of lipids remodeling in the plant membranes under different environmental conditions, e.g., nutrient deficiency, temperature stress, salinity or drought was proved. The key advantage of lipid research was the conclusion that lipids could serve as the markers of plant physiological condition and the detailed knowledge on lipids chemistry will allow to modify their composition for industrial needs.

show abstract

Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response

Cited by 22 publications

References 42 publications

Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids

Human Cytomegalovirus Uses a Host Stress Response To Balance the Elongation of Saturated/Monounsaturated and Polyunsaturated Very-Long-Chain Fatty Acids

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Lipids Composition in Plant Membranes

Contact Info

Product

Resources

About