Identification of a New Cholesterol‐Binding Site within the IFN‐<i>γ</i> Receptor that is Required for Signal Transduction

Morana, Ornella; Nieto-Garai, Jon Ander; Björkholm, Patrik; Serna, Jorge Bernardino de la; Terrones, Oihana; Arboleya, Aroa; Ciceri, Dalila; Rojo-Bartolomé, Iratxe; Blouin, Cédric M.; Lamaze, Christophe; Lorizate, Maier; Contreras, F.‐Xabier

doi:10.1002/advs.202105170

Cited by 11 publications

(9 citation statements)

References 78 publications

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“…Accordingly, a potent SM binding motif was reported in the transmembrane domain of the IFN-γR1 subunit (Contreras et al, 2012). More recently, we have characterized a new Chol binding motif in the IFN-γR2 transmembrane domain, and we found it to be mandatory for IFN-γR activation and signaling (Morana et al, 2022). While the direct relationship between formins and SM-dependent lipid nanodomains has not been established, it has been proposed that short dynamic actin filament structures known as “actin asters”, that are driven by RhoA-dependent acto-myosin contractility, regulate lipid nanodomain formation and receptor activation at the plasma membrane (Kalappurakkal et al, 2019; Wang, et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

Dia2 formin controls receptor activity by organizing plasma membrane lipid partitioning at the nanoscale

Li,

Hamon,

Mazaud

et al. 2023

Preprint

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Activation of JAK/STAT signaling by IFN-γ requires partitioning of IFN-γR into specific lipid nanodomains at the plasma membrane. Using IFN-γR as a proxy, we investigated the role of actin dynamics in the formation and organization of lipid nanodomains, a process that remains poorly understood. We identified formin Dia2/DIAPH3 as a specific and RhoA -dependent regulator of IFN-γ-induced JAK/STAT signaling. Based on lipidomics and specific probes enabling membrane lipid imaging by super resolution microscopy, we demonstrate that Dia2 is required for proper assembly of sphingomyelin and cholesterol lipid complexes. Finally, we show that the disorganization of lipid nanodomains induced by Dia2 depletion results in drastic changes in nano-partitioning and activity of other membrane proteins, such as Thy1 and PD-L1. Our data establish, therefore, the central role of the RhoA-Dia2 axis in the regulation of IFN-γ induced JAK/STAT signaling, and more broadly, in the nanoscale organization of the plasma membrane.

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Section: Resultsmentioning

confidence: 99%

Dia2 formin controls receptor activity by organizing plasma membrane lipid partitioning at the nanoscale

Li,

Hamon,

Mazaud

et al. 2023

Preprint

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“…Bearing with this knowledge butyrate also shows increased mucin secretion in the gut by exocytosis [ 67 ]. Membrane cholesterol is required for IFN-γ signalling [ 68 ]. Butyrate which we demonstrate as cholesterol decreasing agent is also reported to inhibit IFN-γ signalling [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Butyrate driven raft disruption trots off enteric pathogen invasion: possible mechanism of colonization resistance

et al. 2023

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The gut microbiome derived short chain fatty acids perform multitude of functions to maintain gut homeostasis. Here we studied how butyrate stymie enteric bacterial invasion in cell using a simplistic binary model. The surface of the mammalian cells is enriched with microdomains rich in cholesterol that are known as rafts and act as entry points for pathogens. We showed that sodium butyrate treated RAW264.7 cells displayed reduced membrane cholesterol and less cholera-toxin B binding coupled with increased membrane fluidity compared to untreated cells indicating that reduced membrane cholesterol caused disruption of lipid rafts. The implication of such cellular biophysical changes on the invasion of enteric pathogenic bacteria was assessed. Our study showed, in comparison to untreated cells, butyrate-treated cells significantly reduced the invasion of Shigella and Salmonella, and these effects were found to be reversed by liposomal cholesterol treatment, increasing the likelihood that the rafts' function against bacterial invasion. The credence of ex vivo studies found to be in concordance in butyrate fed mouse model as evident from the significant drift towards a protective phenotype against virulent enteric pathogen invasion as compared to untreated mice. To produce a cytokine balance towards anti-inflammation, butyrate-treated mice produced more of the gut tissue anti-inflammatory cytokine IL-10 and less of the pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ. In histological studies of Shigella infected gut revealed a startling observation where number of neutrophils infiltration was noted which was correlated with the pathology and was essentially reversed by butyrate treatment. Our results ratchet up a new dimension of our understanding how butyrate imparts resistance to pathogen invasion in the gut.

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“…The pinhole was set to one Airy unit. Optimized acquisition was performed to retrieve protein membrane diffusion values as described previously [14, 15]. Images of 256 × 256 pixels at 8-bit depth were collected using 80 nm pixel size and 5 μsec dwell time, for 250 consecutive frames.…”

Section: Methodsmentioning

confidence: 99%

An examination of the divergent spatiotemporal signaling of GLP-1R versus GIPR in pancreatic beta cells

Manchanda

Bitsi

Chen

et al. 2022

Preprint

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The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), are class B GPCRs and prime therapeutic targets for the treatment of type 2 diabetes (T2D) and obesity. They are expressed in pancreatic beta cells where they potentiate insulin release in response to food intake. Despite GIP being the main incretin in healthy individuals, GLP-1R has been favoured versus GIPR as a therapeutic target due to GIPR responses being blunted in T2D patients and the conflicting effects of GIPR agonists and antagonists in improving glucose tolerance and preventing weight gain. There is, however, a recently renewed interest in GIPR biology following the realisation that GIPR responses can be restored after an initial period of blood glucose normalization and the recent development of dual GLP-1R-GIPR agonists with superior capacity for the control of blood glucose levels and weight. The importance of GLP-1R trafficking and subcellular signaling in the control of receptor outputs is well established, but little is known about the pattern of spatiotemporal signaling from the GIPR in beta cells. Here we have directly compared the main trafficking and signaling characteristics of both receptors in pancreatic beta cells, finding striking differences in their propensities for internalization, recycling, and degradation, as well as plasma membrane versus endosomal activity, with potential implications for receptor-specific control of beta cell function.

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Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction

Cited by 11 publications

References 78 publications

Dia2 formin controls receptor activity by organizing plasma membrane lipid partitioning at the nanoscale

Dia2 formin controls receptor activity by organizing plasma membrane lipid partitioning at the nanoscale

Butyrate driven raft disruption trots off enteric pathogen invasion: possible mechanism of colonization resistance

An examination of the divergent spatiotemporal signaling of GLP-1R versus GIPR in pancreatic beta cells

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