Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor

Mata, Miguel A.; Satterly, Neal; Versteeg, Gijs A.; Frantz, Doug E.; Wei, Shuguang; Williams, Noelle S.; Schmolke, Mirco; Peña-Llopis, Samuel; Brugarolas, James; Forst, Christian V.; White, Michael A.; Garcı́a-Sastre, Adolfo; Roth, Michael G.; Fontoura, Beatriz M. A.

doi:10.1038/nchembio.645

Cited by 69 publications

(82 citation statements)

References 46 publications

(51 reference statements)

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“…3A). The decay of REDD1 mRNA (Fig 3B) is in accordance with the half-life of approximately 30 min described by Mata et al [33]. However, IL-6 does not decrease REDD1 mRNA stability (Fig.…”

Section: Discussionsupporting

confidence: 75%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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“…3A). The decay of REDD1 mRNA (Fig 3B) is in accordance with the half-life of approximately 30 min described by Mata et al [33]. However, IL-6 does not decrease REDD1 mRNA stability (Fig.…”

Section: Discussionsupporting

confidence: 75%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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“…Given the importance of NS1-mediated host mRNA export block to favor viral replication, NS1 is seen as an attractive target for development of novel antiviral therapeutics and for probing novel cellular mechanisms. In the last few years, high throughput screens were performed to identify small molecules that could antagonize NS1-mediated inhibition of host gene expression [51,52]. In one screen, an NS1 antagonist was shown to rescue interferon expression by NS1 thereby restoring antiviral response [51].…”

Section: Mrna Export In Viral Infection and Metabolismmentioning

confidence: 99%

“…This effect would lead to expression of mRNAs encoding antiviral factors, which would contribute to the restoration of antiviral response. In another screen, an antagonist of NS1 inhibited replication of VSV and influenza virus by inducing the expression of REDD1, an inhibitor of the mTORC1 pathway that is required for influenza virus replication [52,53]. The relationship between this mechanism and the effect of NS1 on nucleocytoplasmic trafficking is not yet known.…”

Section: Mrna Export In Viral Infection and Metabolismmentioning

confidence: 99%

Nuclear Trafficking in Health and Disease

Mor¹,

White²,

Fontoura³

2014

Current Opinion in Cell Biology

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In eukaryotic cells, the cytoplasm and the nucleus are separated by a double-membraned nuclear envelope (NE). Thus, transport of molecules between the nucleus and the cytoplasm occurs via gateways termed the nuclear pore complexes (NPCs), which are the largest intracellular channels in nature. While small molecules can passively translocate through the NPC, large molecules are actively imported into the nucleus by interacting with receptors that bind nuclear pore complex proteins (Nups). Regulatory factors then function in assembly and disassembly of transport complexes. Signaling pathways, cell cycle, pathogens, and other physiopathological conditions regulate various constituents of the nuclear transport machinery. Here, we will discuss several findings related to modulation of nuclear transport during physiological and pathological conditions, including tumorigenesis, viral infection, and congenital syndrome. We will also explore chemical biological approaches that are being used as probes to reveal new mechanisms that regulate nucleocytoplasmic trafficking and that are serving as starting points for drug development.

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“…It is a host defence factor against RNA viruses (Mata et al, 2011). It is implicated in neurogenesis and neurodegenerative diseases (Malagelada et al, 2011) and controls Schwann cell myelination in mice (Noseda et al, 2013).…”

Section: The Importance Of the Redd1 Nt Domainmentioning

confidence: 99%

Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation

Michel¹,

Matthes²,

Hachet‐Haas³

et al. 2013

Journal of Cell Science

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The mTORC1 kinase promotes cell growth in response to growth factors by activation of receptor tyrosine kinase. It is regulated by the cellular energy level and the availability of nutrients. mTORC1 activity is also inhibited by cellular stresses through overexpression of REDD1 (regulated in development and DNA damage responses). We report the identification of REDD1 in a fluorescent live-imaging screen aimed at discovering new proteins implicated in G-protein-coupled receptor signaling, based on translocation criteria. Using a sensitive and quantitative plasma membrane localization assay based on bioluminescent resonance energy transfer, we further show that a panel of endogenously expressed GPCRs, through a Ca 2+ /calmodulin pathway, triggers plasma membrane translocation of REDD1 but not of its homolog REDD2. REDD1 and REDD2 share a conserved mTORC1-inhibitory motif characterized at the functional and structural level and differ most in their N-termini. We show that the N-terminus of REDD1 and its mTORC1-inhibitory motif participate in the GPCR-evoked dynamic interaction of REDD1 with the plasma membrane. We further identify REDD1 as a novel effector in GPCR signaling. We show that fast activation of mTORC1 by GPCRs correlates with fast and maximal translocation of REDD1 to the plasma membrane. Overexpression of functional REDD1 leads to a reduction of mTORC1 activation by GPCRs. By contrast, depletion of endogenous REDD1 protein unleashes mTORC1 activity. Thus, translocation to the plasma membrane appears to be an inactivation mechanism of REDD1 by GPCRs, which probably act by sequestering its functional mTORC1-inhibitory motif that is necessary for plasma membrane targeting.

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Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor

Cited by 69 publications

References 46 publications

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Nuclear Trafficking in Health and Disease

Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation

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