SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN responses in CD4+ T cells

Kanno, Toshio; Nakajima, Takahiro; Yokoyama, Satoru; Asou, Hikari K.; Sasamoto, Shigemi; Kamii, Yasuhiro; Hayashizaki, Koji; Ouchi, Yasuo; Onodera, Taishi; Takahashi, Yoshimasa; Ikeda, Kazutaka; Hasegawa, Yoshinori; Kinjo, Yuki; Ohara, Osamu; Nakayama, Toshinori; Endo, Yusuke

doi:10.1038/s42003-021-02310-y

Cited by 30 publications

(24 citation statements)

References 39 publications

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“…In addition, TBK1 and IRF3 activation, both downstream effectors of STING, also regulate central metabolic pathways ( Kumari et al., 2016 ; Zhao et al., 2018 ), including fatty acid metabolism ( Tang et al., 2021 ). Conversely, fatty acid biosynthesis pathways have been proposed to participate in controlling antiviral responses through modulation of the expression of interferon-stimulated genes (Isg) ( Kanno et al., 2021 ). While these studies highlight a role of STING activation and ensuing activation of downstream effectors in the maintenance of metabolic homeostasis, there is as of today no indication of a direct role of STING in metabolism.…”

Section: Introductionmentioning

confidence: 99%

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

et al. 2022

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Summary Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

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Section: Introductionmentioning

confidence: 99%

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

et al. 2022

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“…Our data further indicated that selective decrease in monounsaturated fatty acid (MUFA) biosynthesis is crucial for the induction of type I-IFN response in CD4 + T cells ( 18 ). Indeed, CRISPR/Cas9-mediated genome editing of the stearyl-CoA desaturase 2 (Scd2), which is responsible for MUFA biosynthesis, dramatically increased the expression of ISGs in CD4 + T cells ( 18 ). On the other hand, type I-IFN signaling changes the fatty acid oxidization, OXPHOS and expression levels of genes related to lipid metabolism in pDCs and macrophages ( 19 ).…”

Section: Introductionmentioning

confidence: 52%

“…Bensinger et al showed that altering the balance between cholesterol biosynthesis and scavenging, rather than reducing the endogenous lipid pool size, is essential for achieving type I-IFN responses in macrophage ( 17 ). We also previously found that genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase (ACC1), which is rate limiting enzyme of fatty acid biosynthesis, substantially increases the basal expression of ISGs via the spontaneous production of type I-IFN ( 18 ). Our data further indicated that selective decrease in monounsaturated fatty acid (MUFA) biosynthesis is crucial for the induction of type I-IFN response in CD4 + T cells ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

“…We also previously found that genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase (ACC1), which is rate limiting enzyme of fatty acid biosynthesis, substantially increases the basal expression of ISGs via the spontaneous production of type I-IFN ( 18 ). Our data further indicated that selective decrease in monounsaturated fatty acid (MUFA) biosynthesis is crucial for the induction of type I-IFN response in CD4 + T cells ( 18 ). Indeed, CRISPR/Cas9-mediated genome editing of the stearyl-CoA desaturase 2 (Scd2), which is responsible for MUFA biosynthesis, dramatically increased the expression of ISGs in CD4 + T cells ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells

et al. 2022

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Type I interferons (type I-IFN) are critical for the host defense to viral infection, and at the same time, the dysregulation of type I-IFN responses leads to autoinflammation or autoimmunity. Recently, we reported that the decrease in monounsaturated fatty acid caused by the genetic deletion of Scd2 is essential for the activation of type I-IFN signaling in CD4+ Th1 cells. Although interferon regulatory factor (IRF) is a family of homologous proteins that control the transcription of type I-IFN and interferon stimulated genes (ISGs), the member of the IRF family that is responsible for the type I-IFN responses induced by targeting of SCD2 remains unclear. Here, we report that the deletion of Scd2 triggered IRF3 activation for type I-IFN production, resulting in the nuclear translocation of IRF9 to induce ISG transcriptome in Th1 cells. These data led us to hypothesize that IRF9 plays an essential role in the transcriptional regulation of ISGs in Scd2-deleted (sgScd2) Th1 cells. By employing ChIP-seq analyses, we found a substantial percentage of the IRF9 target genes were shared by sgScd2 and IFNβ-treated Th1 cells. Importantly, our detailed analyses identify a unique feature of IRF9 binding in sgScd2 Th1 cells that were not observed in IFNβ-treated Th1 cells. In addition, our combined analyses of transcriptome and IRF9 ChIP-seq revealed that the autoimmunity related genes, which increase in patient with SLE, were selectively increased in sgScd2 Th1 cells. Thus, our findings provide novel mechanistic insights into the process of fatty acid metabolism that is essential for the type I-IFN response and the activation of the IRF family in CD4+ T cells.

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“…The expression level of several IFN-related cytokines, including IRF3, IRF7 and ISG15, as well as that of proinflammatory cytokines, such as IL-6, IL-8 and TNFα, were all significantly increased. Increased research has demonstrated that inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferons (IFN) [39]. The lack of ω-3 FAs could disturb lipid metabolism homeostasis and thus induced proinflammation metabolites synthesis [40].…”

Section: Discussionmentioning

confidence: 99%

SGIV Induced and Exploited Cellular De Novo Fatty Acid Synthesis for Virus Entry and Replication

Zheng

Huang

Wang

et al. 2022

Viruses

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Considerable attention has been paid to the roles of lipid metabolism in virus infection due to its regulatory effects on virus replication and host antiviral immune response. However, few literature has focused on whether lipid metabolism is involved in the life cycle of lower vertebrate viruses. Singapore grouper iridovirus (SGIV) is the causative aquatic virus that extensively causes fry and adult groupers death. Here, the potential roles of cellular de novo fatty acid synthesis in SGIV infection was investigated. SGIV infection not only increased the expression levels of key enzymes in fatty acid synthesis in vivo/vitro, including acetyl-Coenzyme A carboxylase alpha (ACC1), fatty acid synthase (FASN), medium-chain acyl-CoA dehydrogenase (MCAD), adipose triglyceride lipase (ATGL), lipoprotein lipase (LPL) and sterol regulatory element-binding protein-1 (SREBP1), but it also induced the formation of lipid droplets (LDs), suggesting that SGIV altered de novo fatty acid synthesis in host cells. Using the inhibitor and specific siRNA of ACC1 and FASN, we found that fatty acid synthesis was essential for SGIV replication, evidenced by their inhibitory effects on CPE progression, viral gene transcription, protein expression and virus production. Moreover, the inhibitor of fatty acid β-oxidation could also reduce SGIV replication. Inhibition of fatty acid synthesis but not β-oxidation markedly blocked virus entry during the life cycle of SGIV infection. In addition, we also found that inhibition of ACC1 and FASN increased the IFN immune and inflammatory response during SGIV infection. Together, our data demonstrated that SGIV infection in vitro regulated host lipid metabolism and, in that process, cellular fatty acid synthesis might exert crucial roles during SGIV infection via regulating virus entry and host immune response.

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SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN responses in CD4+ T cells

Cited by 30 publications

References 39 publications

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells

SGIV Induced and Exploited Cellular De Novo Fatty Acid Synthesis for Virus Entry and Replication

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