Membrane & Immunity Team (Franck Fieschi)

Team leader: Franck FIESCHI (Professor, UGA)

Introduction

The functioning of the immune system involves many stages of cell-cell interaction, host-pathogen, and cell activation for the initiation of the immune response, which require a diversified arsenal of membrane proteins that differ from one cell type to another. Because of their roles in human health, these proteins are of major interest for both fundamental and for applied medical research. Despite the methodological pitfalls of working on eukaryotic membrane proteins, we are committed investigating two major protein families: C-type lectin receptors (CLRs) and NADPH oxidase from the NOX Family. CLRs recognize saccharide patterns as non-self or self-altered and modulate the associated immune response. NOX enzymes generate reactive oxygen species used as a cytotoxic agent and also for signaling in many tissues; misregulation leads to oxidative stress and diseases.

NADPH oxidases from the NOX Family (NOXs).

  • Eukaryotic NOX Enzymes.

– Contact: Marie José Stasia, Franck FIESCHI.
– Involved staff: Michel Thépaut, Isabelle Hartlein & Perrine Rochas.

NOXs enzymes are membrane redox enzymes involved in the production of reactive oxygen species (ROS). Indeed, NOX’s enzymes and their ROS products are involved in many physiological function of primary importance (cardiovascular tone regulation, hormone synthesis, balance, fertility…) making them interesting target for many pharmaceutical companies. Notably, NOX has been initially identified as a key factor for innate immunity as illustrated in Chronic Granulomatous Disease (CGD). CGD is an inherited immunodeficiency in which patients lack a functional NOX2. From mutations identified in patients, we analyzed recombinantly reproduced versions and identified an important interface between the two subunits of the NOX complex. Marie José Stasia in the group leads a CGD diagnostic center at CHU Grenoble Alps.

  • Prokaryotic NOX Homologs.

– Contact: Franck FIESCHI.
– Involved staff: Michel Thépaut, Isabelle Hartlein.

To aid in elucidating the molecular mechanisms and structures of NOXs, we developed studies on prokaryotic NOX homologs. We are focusing on production and characterization of the Streptococcus pneumonia NOX (SpNox). Part of this work is made in partnership with Pr. Susan Smith from KSU, Georgia-USA (invited Professor at IBS).
We also identified another bacterial homolog MsrQP, which exists as two distinct proteins corresponding to the two domains of NOXs that could be involved in bacterial virulence.

Collaborations:
– Vincent Nivière, CEA, Grenoble.
– Dominique Durand, Marie Erard, Paris XI University, Orsay.
– Karl-Heinz Krause, Genève University, Switzerland.
– Max Maurin, CHU, Grenoble.
– José Márquez, EMBL, Grenoble.

Host-pathogen interactions: C-type lectin receptors (CLRs).


– Contact: Franck Fieschi.
– Involved staff: Michel Thépaut, Clara Delaunay.

CLRs are pathogen recognition receptors essential to immune system for recognition and signaling. CLRs recognize specific carbohydrate-based motifs and play a critical role in the processes leading to antigen presentation by dendritic cells. Different CLRs recognize different patterns, inducing either activation or repression of the immune response. However, pathogens like HIV and M. tuberculosis can hijack CLRs and evade the immune system. CLRs can be targeted, depending on the context, for vaccination strategies, immune activation, anti-infective agents, etc., making them attractive for drug discovery.

  • Development of recombinant production of human CLRs: actually 10 different human lectins.
  • Development of new tools: artificial multivalent lectins.
  • Ligand optimization and screening approaches: glycan arrays, glycomimetic arrays.
  • Structural characterization of receptor/ligand complexes.

Collaborations:
– Javier Rojo, Instituto de Investigaciones Quimicas, Sevilla, Spain.
– Anna Bernardi, University of Milano, Italy.
– Niels Reichardt, CIC biomaGUNE, San Sebastian, Spain.
– Peter H. Seeberger, Bernd Lepenies and Christoph Rademacher, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
– Jean-Pierre Simorre and Cédric Laguri, IBS, Grenoble.
– Antonio Molinaro, University of Naples Federico II, Italy.
– Franck Halary, University of Nantes.
– Yoann Rombouts, Institute of Pharmacology and Structural Biology, Toulouse.
– Jean-Luc Coll, Institute for Advanced Biosciences, Grenoble.
– Olivier Renaudet, University of Grenoble.
– Pedro Manuel Nieto Mesa and Jesus Angulo, Institute for Chemical Research (IIQ), Sevilla, Spain.
– Anne Imberty, CERMAV, Grenoble.

Patent

Dupuy J, Hajjar C, Cherrier M, Fieschi F.
NADPH oxidase proteins.
WO/2015/162383 (2015).