TECR (trans-2-enoyl-CoA reductase), VLCFAs and sphingolipids in ME

Very long-chain fatty acids (VLCFAs) are fatty acids (FAs) with a chain-length of ≥22 carbons. Mammals have a variety of VLCFAs differing in chain-length and the number of double bonds. Each VLCFA exhibits certain functions, for example in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function and anti-inflammation. These functions are elicited not by free VLCFAsthemselves, but through their influences as components of membrane lipids (sphingolipids and glycerophospholipids) or precursors of inflammation-resolving lipid mediators. VLCFAs are synthesized by endoplasmic reticulum membrane-embedded enzymes through a four-step cycle. The most important enzymes determining the tissue distribution of VLCFAs are FA elongases, which catalyze the first, rate-limiting step of the FA elongation cycle. Mammals have seven elongases (ELOVL1-7), each exhibiting a characteristic substrate specificity. Several inherited disorders are caused by mutations in genes involved in VLCFA synthesis or degradation (1).

FAs are elongated by endoplasmic reticulum (ER) membrane-embedded enzymes following their conversion to acyl-CoAs. FA elongation occurs by cycling through a four-step process: condensation, reduction, dehydration and reduction (1).

Fig. 2. from ref 2: Mammalian FA elongation cycle. The FA elongation cycle and enzymes involved in each step are illustrated. In each cycle, acyl-CoA incorporates two carbon units from malonyl-CoA.

In the last reduction step, trans-2-enoyl-CoA is converted to acyl-CoA, which is longer than the original acyl-CoA by two carbons. The trans-2-enoyl-CoA reductase responsible for this reaction is TER (also known as TECR), and the reaction requires NADPH as a cofactor (Moon and Horton, 2003 from ref 2).

TER is involved in both the production of VLCFAs used in the fatty acid moiety of sphingolipids as well as in the degradation of the sphingosine moiety of sphingolipids via S1P (3).

An impaired TER function affects VLCFA synthesis and thereby alters the cellular sphingolipid profile. Maintenance of a proper VLCFA level may be important for neural function (4).

The levels of sphingolipids and glycerolipids in plasma from ME patients are dysregulated (5).

The gene TECR (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients. This DNA methylation  is related to quality of life in the ME patients (table S7 in ref 6).

TECR is differentially methylated in PBMC from ME patients subtypes (table S3 in ref 7).

The gene TECR is hypomethylated in PBMC from ME patients (table S4 in ref 8).

TECR is located on chromosome 19 together with mir 639 (9):

Chromosome 19 - NC_000019.10

mir 639 is hypomethylated in CD4+ T cells from ME patients (10).

References

1) Akio Kihara: Very long-chain fatty acids: elongation, physiology and related disorders The Journal of Biochemistry, Volume 152, Issue 5, 1 November 2012, Pages 387–395,https://doi.org/10.1093/jb/mvs105
https://academic.oup.com/jb/article/152/5/387/2182729

2) Sassa and Kihara: Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology. Biomol Ther (Seoul). 2014 Mar; 22(2): 83–92.
doi: [10.4062/biomolther.2014.017]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975470/

3) Wakashima et al: Dual functions of the trans-2-enoyl-CoA reductase TER in the sphingosine 1-phosphate metabolic pathway and in fatty acid elongation. J Biol Chem. 2014 Sep 5;289(36):24736-48. doi: 10.1074/jbc.M114.571869. Epub 2014 Jul 21.
https://www.ncbi.nlm.nih.gov/pubmed/25049234

4) Abe et al: Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile. J Biol Chem. 2013 Dec 20;288(51):36741-9. doi: 10.1074/jbc.M113.493221. Epub 2013 Nov 12.

https://www.ncbi.nlm.nih.gov/pubmed/24220030

5) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

6) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

7) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

8) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

9) Gene mir 639:https://www.ncbi.nlm.nih.gov/gene/693224

10) Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228 https://www.omicsonline.org/open-access/methylation-profile-of-cd-t-cells-in-chronic-fatigue-syndromemyalgic-encephalomyelitis-2155-9899.1000228.php?aid=27598

The role of endoplasmic reticulum-mitochondria contact sites

The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving (1).

MAMs are now considered as structural platform for an optimal bioenergetics response allowing cellular adaptations to environmental changes. Indeed, the transfer of Ca2+from ER to mitochondria is crucial for the control of mitochondria energy metabolism, since mitochondrial Ca2+ levels control the activity of Krebs cycle’s deshydrogenases and impact ATP synthesis (Fig. ​(Fig.2).2 from ref 1).

Fig. 2 from ref 1:  Key components and functions of MAMs involved in the control of glucose homeostasis. ER-mitochondria contact sites shelter several components that impact glucose homeostasis either indirectly by regulating mitochondria biology, UPR signaling and autophagy and immune signalling, or more directly by controlling insulin signaling.

Metabolic regulations are tightly coupled with inflammation and immune responses and exacerbated inflammatory responses have been linked to metabolic diseases. ER-mitochondria contact sites were recently found to be an important actor of the cellular anti-viral response (Fig. 2).

During the inflammatory response, NLRP3 and other inflammasome members move to the MAM to coordinate the appropriate response. Calcium sensing receptor (CASR) activates the NLRP3 inflammasome through phospholipase C, which catalyzes IP3 production and thereby induces the release of Ca2 +from the ER (2). TRPM2 is also involved in NLRP3 activation (3).

The distance between the ER and (outer mitochondrial membrane (OMM) is a critical factor in the efficient transfer of Ca2 +. Aside from the spacing between the two organelles, the contact volume is another important parameter in the regulation of Ca2 + signaling. (2) FHIT overexpression enhances the number of these ER–mitochondria hot spots, favoring mitochondrial Ca2 +accumulation and triggering Ca2 +-dependent apoptosis ( [53] in ref 2).

GIMAP5 is a key regulator of hematopoietic integrity and lymphocyte homeostasis. GIMAP5 has a role in maintaining peripheral tolerance and T cell homeostasis in the gut (4). GIMAP5 alsp functions at the MAM (1).

Phosphatidylserine (PS) is synthesized in ER by the exchange of serine for the choline or ethanolamine head-groups of phosphatidylcholines (PC) or phosphatidylethanolamines (PE) by PS synthase-1 and PS synthase−2, which are enriched at MAMs (ref 24 in ref 1). Then, newly-made PS is transferred into mitochondria through MAMs, where it is decarboxylated to PE via PS decarboxylase in mitochondrial inner membrane (ref 25 in ref 1). PS transfer at MAM interface is mediated by oxysterol-binding proteins-related protein 5 (ORP5) and ORP8, which were also localized at MAMs (ref 26 in ref 1).

The above mentioned proteins (CASR, FHIT, GIMAP5, NLRP3, PML, ORP5, ORP8, TRPM2) are encoded by genes which show up with changed DNA methylation pattern in PBMC from ME patients in either one or several studies (5, 6, 7, 8).

References: 

1) Rieusset:  The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update. Cell Death Dis. 2018 Mar; 9(3): 388.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844895/

2) Marchi et al: The endoplasmic reticulum–mitochondria connection: One touch, multiple functions. Biochimica et Biophysica Acta (BBA) - Bioenergetics
Volume 1837, Issue 4, April 2014, Pages 461-469

https://www.sciencedirect.com/science/article/pii/S0005272813001850?via%3Dihub

3) Zhong et al: TRPM2 links oxidative stress to NLRP3 inflammasome activation Nat Commun. 2013;4:1611. doi: 10.1038/ncomms2608. https://www.ncbi.nlm.nih.gov/pubmed/23511475

4) GIMAP5: https://www.ncbi.nlm.nih.gov/gene/246774

5) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8

6) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

7) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

8) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

PACS2 and ME

Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease (1).

Figure 1: Global view of the architecture/choreography of ER–mitochondria contacts. As depicted, a part of ER tubule and mitochondria form quasi-synaptic structure. Several pairs of integral membrane proteins located on mitochondria and ER important for MERC formation and physical tethering of the organelles were identified, including Mfn1/2 tether, Fis1-Bap31 tether, VAPB-PTPIP51 tether and IP3R-grp75-VDAC1 tripartite complex. The latter is essential for the efficient Ca2+ transfer from the ER to mitochondria. MAM: mitochondria associated ER membrane, OMM = outer mitochondrial membrane, IMM: inner mitochondrial membrane, Mx = matrix, ETC: electron transport chain, TAC: tricarboxylic acid cycle  Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases Transl Neurodegener. 2017;6:21. (ref 1).

Figure 1 shows phosphorin acidic cluster sorting protein 2 (PACS2). PACS2 modulates the Fis1-Bap31 tether (1).

PACS2 is a multifunctionel protein involved in (2): 

• membrane trafficking
• MAM-localized ca2+ signaling
• switching between anabolic and catabolic roles of the MAM
• p53-p21-dependent cell cycle arrest
• apoptosis
• lipid metabolism
• regulating recycling of the metalloproteinase ADAM17
• subcellular distribution of calnexin

PACS2 functions as a metabolic switch that integrates traffic and interorganellar communication with nuclear gene expression in response to anabolic or catabolic cues (2).

Viruses can hijack the PACS2 pathway (2).

The gene PACS2 (TSS1500) is differentially methylated in PBMC from ME patients subtypes (3).

References 

1) LIU and Zhu: Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases.

Transl Neurodegener. 2017; 6: 21.

Published online 2017 Aug 23. doi:  10.1186/s40035-017-0092-6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567882

2) Thomas et al. Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease.J Cell Sci. 2017 Jun 1;130(11):1865-1876. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482974/

3)  de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

MGRN1 and ME

Mahogunin ring finger 1 (MGRN1) is a cytosolic ubiquitin ligase.

MGRN1 expression increases when cells are exposed to a variety of stressors.

Mice lacking MGRN1 have reduced level of many mitochondrial proteins. They have mitochondrial dysfunction and develop neurodegeneration.

MGRN1 is involved in:

• mitochondrial fusion
• mitochondrial trafficking via regulation of microtubules
• regulation af ER-associated protein degradation and ER-mitochondria junctions via interaction with the ligase GP78

(Ref1-5)

Four studies have shown the gene MGRN1 is differentially methylated in PBMC from ME patients compared to controls (6, 7, 8, 9). The DNA methylation pattern is related to quality of life in the ME patients (7) and is related to ME patient subtypes (8).

References:

1) Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice.
Sun K, Johnson BS, Gunn TM.
Neurobiol Aging. 2007 Dec;28(12):1840-52. Epub 2007 Aug 27.
PMID: 17720281

2) Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system.
Mukherjee R, Bhattacharya A, Sau A, Basu S, Chakrabarti S, Chakrabarti O.
FASEB J. 2018 Sep 19:fj201701413RRR. doi: 10.1096/fj.201701413RRR. [Epub ahead of print]
PMID: 30230921

3) Ubiquitin-mediated regulation of the E3 ligase GP78 by MGRN1 in trans affects mitochondrial homeostasis.
Mukherjee R, Chakrabarti O.
J Cell Sci. 2016 Feb 15;129(4):757-73. doi: 10.1242/jcs.176537. Epub 2016 Jan 7.
PMID: 26743086

4) Regulation of Mitofusin1 by Mahogunin Ring Finger-1 and the proteasome modulates mitochondrial fusion.
Mukherjee R, Chakrabarti O.
Biochim Biophys Acta. 2016 Dec;1863(12):3065-3083. doi: 10.1016/j.bbamcr.2016.09.022. Epub 2016 Oct 4.
PMID: 27713096

5).MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport.Mukherjee R, Majumder P, Chakrabarti O.
Traffic. 2017 Dec;18(12):791-807. doi: 10.1111/tra.12527. Epub 2017 Oct 4.PMID: 28902452

6) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8

7) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

8) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

9) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

H2AFY and ME

H2AFY (also known as macroH2A1) is a histone H2A variant. It replaces conventional H2A histones in a subset of nucleosomes.

This gene encodes two splice isoforms, H2AFY1.1 and H2AFY1.2 (also known as mH2A1.1 and mH2A1.2). mH2A1.1 and mH2A1.2 are produced by mutually exclusive use of exons 6b and 6a.  The isoforms have distinct regulatory properties.

H2AFY, ZFR and interferon signaling

ZFR (zinc finger RNA binding protein)  coordinates crosstalk between RNA decay and transcription in innate immunity.

ZFR protein is required for H2AFY expression. ZFR regulates alternative splicing and decay of H2AFY mRNA.

ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay of histone variant macroH2A1/H2AFY mRNAs (1).

Figure from reference 1: Model for ZFR-mediated regulation of IFNβ. ZFR is required for productive splicing of mH2A1. In the absence of ZFR, mH2A1 pre-mRNA is mis-spliced and resulting transcript is degraded by NMD. In the presence of ZFR, mH2A1 protein is expressed and directly represses the IFNB1 promoter (1).

MacroH2A1.1 regulates mitochondrial respiration

MacroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites.

MacroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and  myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity (2).

H2AFY and B-cells

The H2AFY1.1 isoform is important for B cell development. Reduction in this isoform may contribute to abnormal hematopoiesis (3).

H2AFY in ME

DNA methylation pattern in the gene H2AFY in peripheral blood mononuclear cells (PBMC) from ME patients:

de Vega 2017(table S7 in ref 4): TSS200, TSS1500 and body are hypermethylated

de Vega 2018 (table S3 in ref 5): Five different probes (rank 96, 229, 277, 711 and 965) show the gene is differentially methylated in ME patients subtypes

Trivedi 2018 (table S6 in ref 6): The gene promoter is hypomethylated

Trivedi 2018 (table S4 in ref 6): Thirteen different probes show that TSS1500 and 3'UTR are hypomethylated

Why is H2AFY hypermethylated in de Vega's study and hypomethylated in Trivedi's study?

H2AFY isoform 2 content in cerebrospinal fluid (7):
1) Controls: no value
2) ME patients: 3
3) Post treatment Lyme patients: 5

What does H2AFY do in ME?

References: 

1) Hauque et al. ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nature Communicationsvolume 9, Article number: 1145 (2018)

https://www.nature.com/articles/s41467-018-03326-5
Figure: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861047/figure/Fig7/

2)  Marjanovic et al. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nature Structural & Molecular Biology,  volume 24, pages902–910 (2017)
https://www.nature.com/articles/nsmb.3481

3) Sanghyun Kim, Monique Chavez, Cara Shirai and Matt Walter. Abstract 5108: The role of H2afy in normal and malignant hematopoiesis.  DOI: 10.1158/1538-7445.AM2018-5108 Published July 2018 http://cancerres.aacrjournals.org/content/78/13_Supplement/5108.short

4) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

5) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

6) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.

 Plos One 2018, 13, 7   https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

7) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

CLYBL, itaconate and B12 - involved in ME?

The gene citrate lyase subunit beta-like (CLYBL) is a mitochondrial enzyme (1).

Figure 1. A Novel Pathway Linked to Vitamin B12 Metabolism. 

The metabolic role of CLYBL is linked to B12 metabolism and the immunomodulatory metabolite, itaconate (1).

CLYBL in ME

The gene CLYBL (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients (table S1 in ref 2).

Some ME patients have single nucleotide polymorphism  (SNP) in the gene CLYBL (3). 

CLYBL, itaconate and B12

CLYBL participates in a relatively unexplored human C5 metabolic pathway.

CLYBL is required for maintaining mitochondrial B12 function.

Immunoresponsive gene 1 (IRG1) is expressed exclusively in activated macrophages. IRG1 produce itaconate through decarboxylation of cis-aconitate, a TCA-cycle intermediate.

In vitro test showed that itaconate added to human B-lymphocytes were converted to itaconyl-CoA inside the cells and dramatically lowered B12.

High concentrations of macrophage-derived itaconate might have autocrine and paracrine effects and poison B12 in nearby tissues, raising the possibility for a localized vitamin deficiency in the setting of inflammation (4). 

The B12 regulation may have important implications for other metabolic pathways and pathophysiological contexts. Serine, glycine and one-carbon (SGOC) metabolism, which requires B12 to couple the methionine and folate cycles, is important for nucleotide biosynthesis, redox homeostasis and methylation reactions (1, 4).

SGOC metabolism in ME

Naviaux et al have described  dysregulated SGOC metabolism in ME patients (ref 5 - do take a look at figure S6 in the article supplementary).

B12 in ME

Some ME patients respond to B12/folic acid support (6).

Further reading about STING and itaconate: 

Is STING involved in ME? http://followmeindenmark.blogspot.com/2018/10/is-sting-involved-in-me.html

References: 

1) A Missing Link to Vitamin B12 Metabolism.

• Michael J. A. Reid, Jihye Paik, Jason W. Locasale
• Published 2017 in Cell
• DOI:10.1016/j.cell.2017.10.030

https://www.semanticscholar.org/paper/A-Missing-Link-to-Vitamin-B12-Metabolism.-Reid-Paik/aec86264a4fb0a28865ef026ace7d772b25f1114/figure/0

2) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

3) Smith et al: Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology. 2011;64(4):183-94. doi: 10.1159/000326692. Epub 2011 Sep 9.
 https://www.ncbi.nlm.nih.gov/pubmed/21912186 

4) Shen et al: The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12. Cell, 171, 771-782, 2017
https://www.sciencedirect.com/science/article/pii/S0092867417311820

5) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480.   https://doi.org/10.1073/pnas.1607571113 

6) Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124648

Is STING involved in ME?

NEW RESEARCH

Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling

Abstract:The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory disease (1).

The gene TMEM173 encodes STING.

TMEM173 is hypermethylated (genic location: body, p-value = 4,53E-05, FDR =  0,000816) in peripheral blood mononuclear cells (PBMC) from ME patients compared to controls (2).

TMEM173 is differentially methylated (genic location: 3'UTR, p-value = 7,25E-05, FDR = 0,000184) in PBMC from ME patient subtypes (3).

This DNA methylation pattern is related to degree of disease and quality of life in the ME patients (2, 3).

Is STING (TMEM173) involved in the pathomechanism in ME patient subtypes?

ME patents are metabolic reprogrammed (4, 5, 6, 7). Is a downregulated Nrf2 involved in a STING-pathomechanism in ME? Read about Nrf2 and STING in:


Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
Abstract:
The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases (8).

Om STING: 
Fedtstof kan stoppe immunforsvar, der løber løbsk
https://ing.dk/artikel/fedtstof-kan-stoppe-immunforsvar-loeber-loebsk-214342


References:

1) Anne Louise Hansen et al: Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling
PNAS published ahead of print July 30, 2018 https://doi.org/10.1073/pnas.1806239115

2) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

3) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

4)  Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113

5) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371.

6) Nagy-Szakal et al: Insights into ME/CFS phenotypes through comprehensive metabolomics. Nat Sci Rep 2018, 8.

7) Reuter and Evans: Long-chain acylcarnitine deficiency in patients with CFS. Potential involvement of altered carnitine palmitoyltransferase-I-activity. J. Int. Med. 2011, 270.

8)  David Olangnier et al: Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
Nature Communicationsvolume 9, Article number: 3506 (2018)
https://www.nature.com/articles/s41467-018-05861-7