Actualité - Epigenetics and Genetics

Childhood genetic disease: one sugar too many...

Céline Giustranti
With its receptor “tied” in the wrong part of the cell membrane, the interferon ɤ is no longer able to perform its natural protective cytokine role. This results in a syndrome where severe and often fatal infections occur in young children. A mechanism being screened by Christophe Lamaze and his team, specialists in this key protein in immune defence.
 Dynamique et mécanique membranaires de la signalisation intracellulaire

The interferon ɤ (IFNɤ), is THE cytokin for immune defence. This protein is produced in response to an attack which may be viral, infectious or a tumour. Like all interferons, IFNɤ is likely to trigger an immune reaction when in the presence of a tumour. In concrete terms, once it is produced, IFNɤ binds to a specific receptor present on the surface of some cells and activates the JAK/STAT signalling pathway. Unlike other interferons, IFNɤ has no need to enter the cell to fulfil its role, as shown by the Membrane Dynamics and Mechanics of Intracellular Signalling team (Inserm/CNRS/Institut Curie) of Christophe Lamaze in 2006 (Marchetti et al., MBC 2006). It simply accumulates in nanodomains of the cell membrane to trigger the chain reaction that will result in stimulation of the immune response.

From a meeting to a discovery

Following a lecture by Prof. Jean-Laurent Casanova, an immunologist at the Imagine instutute and Rockefeller University of New York, Christophe Lamaze’s research took on a new dimension. “He had established the key role of IFNɤ in mendelian susceptibility to mycobacterial diseases (MSMD), in which he is a specialist”, explains Christophe Lamaze, Inserm research director at Institut Curie. Children suffering from this genetic disease are susceptible to low virulence mycobacteria, such as Bacillus Calmette-Guérin (BCG) and environmental mycobacteria, and repeatedly suffer from serious infections. “A seemingly unimportant modification to the IFNɤ receptor is responsible for this disease as the receptor is hyperglycosylated”, explains the researcher. “Indeed, in children with this syndrome, instead of having 6 sugars, one of the basic components of the complex, the receptor has 7. This glycosylation alone disrupts the immune response against mycobacteria. It is estimated that glycosylation gains may represent up to 1.4% of genetic diseases”.

The researcher and his team were intrigued and returned to the work bench to study this phenomenon, and thanks to a collaboration with Hai-Tao He’s team from the centre for Immunology at Marseille-Luminy (University Aix Marseille/Inserm/CNRS), and the team of Céline Gales (Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, University of Toulouse III Paul Sabatier, Toulouse), they are gradually revealing more about this mechanism. “The IFNɤ receptor thus altered is no longer located in the correct membrane nanodomain,” explains Christophe Lamaze. “Due to this simple modification, proteins known as galectins displace it by binding to the additional sugar and keep it in a different nanodomain.” The result is that it can no longer activate the JAK/STAT signalling pathway necessary for the protective function of IFNɤ. Furthermore, the addition of excess galectins to the normal IFNɤ receptors causes the same phenomenon. But what is perhaps most interesting to Christophe Lamaze, is that if galectins are removed, the pathological effect associated with the receptor’s glycosylation gain is cancelled out. IFNɤ, like galectins, plays a vital role in the immune response to cancers. These results are an argument for continuing research into the role of galectins in modulation of the body’s anticancer responses.

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Glycosylation-Dependent IFN-γR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation.
Blouin CM, Hamon Y, Gonnord P, Boularan C, Kagan J, Viaris de Lesegno C, Ruez R, Mailfert S, Bertaux N, Loew D, Wunder C, Johannes L,Vogt G, Contreras FX, Marguet D, Casanova JL, Galès C, He HT, Lamaze C.
Cell. 2016 Aug 11; 166(4):920-34. doi: 10.1016/j.cell.2016.07.003. Epub 2016 Aug 4.