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

Hansen, Anne Louise; Buchan, Gregory; Rühl, Michael; Mukai, Kojiro; Salvatore, Sonia R.; Ogawa, Emari; Andersen, Sidsel Dahl; Iversen, Marie B.; Thielke, Anne; Gunderstofte, Camilla; Motwani, Mona; Møller, Charlotte; Jakobsen, Andreas S.; Fitzgerald, Katherine A.; Roos, Jessica; Lin, Rongtuan; Maier, Thorsten J.; Goldbach‐Mansky, Raphaela; Miner, Cathrine A.; Qian, Wei; Miner, Jonathan J.; Rigby, Rachel E.; Rehwinkel, Jan; Jakobsen, Martin R.; Arai, Hiroyuki; Taguchi, Tomohiko; Schöpfer, Francisco J.; Olagnier, David; Holm, Christian K.

doi:10.1073/pnas.1806239115

Cited by 152 publications

(148 citation statements)

References 37 publications

(52 reference statements)

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“…The identified compounds and their derivatives reduce STING mediated inflammatory cytokines production in both human and mouse cells. Furthermore, Hansen et al recently discovered that endogenously formed nitro‐fatty acids can target STING signaling and reduce release of type I IFNs in vitro . Together, these studies have shed light on the potential means of regulating the STING pathway, albeit further studies are still needed to determine whether these interventions are feasible for sepsis patients in clinic.…”

Section: Resultsmentioning

confidence: 99%

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

Knight

Ren

et al. 2018

Acta Physiologica

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Stimulator of interferons genes (STING) is an adaptor protein that plays a critical role in the secretion of type I interferons and pro-inflammatory cytokines in response to cytosolic nucleic acid. Recent research indicates the involvement of the STING pathway in uncontrolled inflammation, sepsis, and shock. STING signaling is significantly up-regulated in human sepsis, and STING agonists are sug-

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Section: Resultsmentioning

confidence: 99%

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

Knight

Ren

et al. 2018

Acta Physiologica

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“…These electrophilic species have a partial positive charge on the  carbon of the vinyl nitro substituent, which supports reversible Michael addition reactions with nucleophilic thiols of GSH and cysteine-containing proteins (16). By altering the structure and function of multiple thiolcontaining transcriptional regulatory proteins, such as NF-kB p65 subunit, Keap1, stimulator of interferon genes (STING), and PPAR-, NO 2 -FAs modulate the expression of more than 300 genes crucial for cytoprotective, metabolic, and anti-inflammatory responses (38)(39)(40). In addition to the electrophilic character of 10-NO 2 -OA, its PK is also influenced by: a) esterification into PLs and TAGs (25,41); b) inactivation upon PtGR-1 reduction to the nonelectrophilic nitroalkane, 10-NO 2 -SA (33); c) and -oxidation reactions to yield shorter chain length dicarboxylate products (27,42); and d) isomerization to the corresponding geometric (Z)-isomer (43).…”

Section: Biodistribution and Metabolism Of 10-no 2 -Oa In Plasma Lipidsmentioning

confidence: 86%

Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Fazzari

Vitturi

Woodcock

et al. 2019

Journal of Lipid Research

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The knowledge of absorption, distribution, metabolism, and excretion (ADME) of new drug candidates is important for safe and insightful development. The rate of drug development failures attributable to ADME deficiencies exceeds 40% and, even after new drug approval, many drugs still display ADME problems. Notably, "a chemical cannot be a drug, no matter how active nor how specific its action, unless it is also taken appropriately into the body (absorption), distributed to the right parts of the body, metabolized in a way that does not instantly remove its activity, and eliminated in a suitable manner" (Ref. 1; p. 722). As a covalently acting endogenous mediator and a class of new drug candidates, electrophilic nitro-fatty acids [NO 2 -FAs (fatty acid nitroalkenes)] have displayed beneficial effects in preclinical animal models of metabolic and inflammatory disease (2-7). A synthetic homolog of a NO 2 -FA detected in plants and mammals (8,9), (E)-10-nitro-octadec-9-enoic acid [10-nitro-oleic acid (10-NO 2 -OA)], is now in phase 2 clinical trials for treating focal segmental glomerulosclerosis and will soon begin trials in pulmonary arterial hypertension and obese asthmatics.NO 2 -FAs are generated during inflammation and digestion by reactions between unsaturated fatty acids and the Abstract Electrophilic nitro-fatty acids [NO 2 -FAs (fatty acid nitroalkenes)] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials. A detailed description of the pharmacokinetics (PK) of NO 2 -FAs is complicated by the capability of electrophilic fatty acids to alkylate thiols reversibly and become esterified in various complex lipids, and the instability of the nitroalkene moiety during enzymatic and base hydrolysis. Herein, we report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously detectable and prototypical NO 2 -FA, 10-nitro-oleic acid (10-NO 2 -OA), in dogs after oral administration. Supported by HPLC-high-resolution-MS/MS analysis of synthetic and plasma-derived 10-NO 2 -OA-containing triacylglycerides (TAGs), we show that a key mechanism of NO 2 -FA distribution is an initial esterification into complex lipids. Quantitative analysis of plasma free and esterified lipid fractions confirmed time-dependent preferential incorporation of 10-NO 2 -OA into TAGs when compared with its principal metabolite, 10-nitro-stearic acid. Finally, new isomers of 10-NO 2 -OA were identified in vivo, and their electrophilic reactivity and metabolism characterized. Overall, we reveal that NO 2 -FAs display unique PK, with the principal mechanism of tissue distribution involving complex lipid esterification, which serves to shield the electrophilic character of this mediator from plasma and hepatic inactivation and thus permits efficient distribution to target organs.-Fazzari, M., D. A. Vitturi, S. R. Woodcock, S. R. Salvatore, B. A. Freeman, and F. J. Schopfer. Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification ...

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“…Activation of the STING signalling pathway with cGAMP requires the ER-to-Golgi traffic of STING and palmitoylation of STING at the Golgi 12,13,18 . We treated cells expressing the α-COP variants with brefeldin A (BFA), an agent to block the ER-to-Golgi traffic 19 , or two palmitoylation inhibitors [a pan-palmitoylation inhibitor 2bromopalmitate (2-BP) and a mouse STING-specific palmitoylation inhibitor C-178 20 ] and found that all the treatments suppressed phosphorylation of TBK1 ( Fig.…”

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confidence: 99%

Homeostatic regulation of STING by Golgi-to-ER membrane traffic

Mukai

Ogawa

Uematsu

et al. 2020

Preprint

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Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi to the ER 1,2 . Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease (COPA syndrome) 3 . The molecular mechanism by which the impaired retrograde transport results in autoinflammation is not understood. Here we report that STING 4 , an innate immunity protein, is a cargo of the Golgi-to-ER membrane transport. In the presence of the diseasecausative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signalling pathway. Surf4 5 , a protein that circulates between the ER and the Golgi, binds STING and α-COP, and mediates retrograde transport of STING to the ER. STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. Intriguingly, the STING ligand cGAMP also impairs the formation of STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by the Golgi-to-ER membrane traffic and provide insights into the pathogenesis of COPA syndrome.

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

Cited by 152 publications

References 37 publications

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Homeostatic regulation of STING by Golgi-to-ER membrane traffic

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