Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

York, Autumn G.; Williams, Kevin J.; Argus, Joseph P.; Zhou, Quan; Brar, Gurpreet; Vergnes, Laurent; Gray, Elizabeth; Zhen, Anjie; Wu, Nicholas C.; Yamada, Douglas H.; Cunningham, Cameron R.; Tarling, Elizabeth J.; Wilks, Moses Q.; Casero, David; Gray, David H.; Yu, Amy K.; Wang, Eric S.; Brooks, David G.; Sun, Ren; Kitchen, Scott G.; Wu, Ting; Reue, Karen; Stetson, Daniel B.; Bensinger, Steven J.

doi:10.1016/j.cell.2015.11.045

Cited by 330 publications

(345 citation statements)

References 49 publications

(62 reference statements)

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“…Our results imply that FAS occurs after type 1 IFN-stimulation in pDCs. These findings diverge from those shown for macrophages that were stimulated with type1 IFNs for 48h, in which long chain FAS was inhibited (York et al, 2015). A directed analysis of lipid synthesis in our system will be required to definitively address these disparities, but it is plausible that: 1) IFN effects differ between cell types; 2) type 1 IFNs induce a biphasic response in which during the first 24h FAS is increased, and thereafter, e.g at 48h, this pathway is diminished, or 3) flux through the FAS pathway is diminished but remains critical.…”

Section: Discussioncontrasting

confidence: 95%

“…Signaling through IFNAR induces the expression of hundreds of Interferon Response Genes (ISGs) (Schneider et al, 2014), which amongst other functions elicit anti-viral programs, and modulate immunity through effects on antigen presenting cells and T cells (Swiecki and Colonna, 2015). Recent reports have indicated that type 1 IFNs affect cellular lipid metabolism by inhibiting de novo cholesterol and fatty acid synthesis and upregulating uptake of exogenous lipids (Blanc et al, 2011; York et al, 2015) and that this is critical for resistance to viral challenge.…”

Section: Introductionmentioning

confidence: 99%

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Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function

et al. 2016

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SUMMARY Greater understanding of the complex host responses induced by type 1 Interferon (IFNs) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO, and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs.

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Section: Discussioncontrasting

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function

et al. 2016

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“…Thus, ER may represent a major battlefield for the host and DENV. Recently, York et al reported that SCAP could modulate STING signaling in response to cholesterol metabolic perturbation (34). Our current study further identified the novel anti-DENV function of SCAP.…”

Section: Discussionsupporting

confidence: 69%

Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation

Liu

Zhang

Jin

et al. 2017

J Virol

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Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave the antiviral protein STING and thereby subvert the innate immune signaling to facilitate virus replication. Whether host cells have a mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked polyubiquitination of NS3 protein facilitates its recruitment of NS2B, the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an endoplasmic reticulum (ER) protein, SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleaving STING. Importantly, ectopic expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP of counteracting the inhibitory action of DENV NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications. IMPORTANCE This study reports the first ubiquitylation target protein in DENV, the NS3 protein, and the unique role of K27-linked polyubiquitylation in NS3's ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING, and the other is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease and thus contribute to host antiviral response.

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“…91 In macrophages, Type-I-IFNs downstream of TLR3 induced a shift in the balance of lipid metabolism away from de novo cholesterol and fatty-acid synthesis in favor of the uptake of exogenous lipids. 92 This immunometabolic circuit is critical for host immune responses. In line with this discovery, TLR9 stimulation in pDCs led to an autocrine IFNAR signaling resulting in an increased fatty-acids oxidation and oxidative phosphorylation, which is key for pDC immune functions.…”

Section: Cancer-extrinsic Effects Of Type-i-ifnsmentioning

confidence: 99%

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

et al. 2017

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If there is a great new hope in the treatment of cancer, the immune system is it. Innate and adaptive immunity either promote or attenuate tumorigenesis and so can have opposing effects on the therapeutic outcome. Originally described as potent antivirals, Type-I interferons (IFNs) were quickly recognized as central coordinators of tumor-immune system interactions. Type-I-IFNs are produced by, and act on, both tumor and immune cells being either host-protecting or tumor-promoting. Here, we discuss Type-I-IFNs in infectious and cancer diseases highlighting their dichotomous role and raising the importance to deeply understand the underlying mechanisms so to reshape the way we can exploit Type-I-IFNs therapeutically.

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Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

Cited by 330 publications

References 49 publications

Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function

Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function

Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

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