DAIH Team: Dysregulation of Autophagy in Inflammation Due to HIV

Autophagy and apoptosis:

GALIG, a human gene embedded in the Galectin-3 gene has been initially described as a proapoptotic gene. It encodes two unrelated proteins, Mitogaligin and Cytogaligin. Proapoptotic properties have been established in relation with Mitogaligin which destabilizes mitochondrial membranes through specific interaction with cardiolipin, a mitochondrial phospholipid. GALIG is underexpressed in bone marrow of patients with Acute Myeloid Leukemia (AML).

Mitogaligin and Cytogaligin have no homology with any other known proteins and their mechanism of action is still poorly understood. Recently, a partial Cytogaligin interactome has been established and reveals that GALIG could be associated with several additional biological functions related to the protein degradation pathways. Indeed, Cytogaligin interacts with several proteins related to autophagy and UPS (Ubiquitin-proteasome system). It interacts also with alpha-synuclein, a major protein in Parkinson’s disease. Our research focuses on the functional consequences of theses interactions in order to determine the potential role of Cytogaligin during autophagy and apoptosis.

We also develop a translational project, in collaboration with several services from the Hospital of Orléans. The objective is to investigate GALIG gene expression and others genes in different pathologies and more specifically in acute myeloid leukemia (AML), Parkinson's disease (PD) and human immunodeficiency (HIV) infection. Preliminary data obtained from AML patients support the potential role of GALIG during differentiation of myeloid cells which is a critical point in the treatment and diagnosis of the disease. In addition, the level of GALIG expression returns to a normal one following chemotherapy treatments. Also, HIV patients exhibit an abnormal level of GALIG gene expression. These results encourage us to further investigate the role of GALIG in AML and HIV infection. Regarding Parkinson’s disease, preliminary data obtained from a small cohort of patients, revealed a clear disturbance of expression of several autophagy genes in peripheral blood. Further investigation are conducted to determine whether such deregulated genes may be considered as a molecular marker for prognostic and diagnostic.

Collaborations on autophagy and apoptosis:

Centre Hospitalier Régional d’Orléans :
- Service de Neurologie, Drs Canan OZSANCAK et Pascal AUZOU
- Services d’Oncologie Médicale et Hématologie Clinique (Pôle Médecines interventionnelles), Drs Michèle SCHOENWALD et Diana CARP.
- Unité de Génétique Dr Sylvain BRIAULT et Thomas GUERY
- Unité d’Hématologie (Pôle Biopathologie), Dr Eric LEGAC.
- Service des Maladies Infectieuses et Tropicales, Drs Laurent HOCQUELOUX et Thierry PRAZUCK.
Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé - CNRS UMR 5236 à Montpellier
- Lucile ESPERT
Université de Franche-Comté, Besançon
- Unité Estrogènes, expression génique et pathologies du système nerveux central (E2SNC), Pr Michaël BOYER-GUITTAUT
Groupe hospitalier l'Archet, Nice
- Service d’Hématologie Clinique, Dr Pierre-Simon ROHRLICH

Main publications:

• Tastet J., Cuberos H., Vallée B., Toutain A., Raynaud M., Marouillat S., Thépault R.-A., Laumonnier F., Bonnet-Brilhault F., Vourc’h P., Andres C. R. and Bénédetti H. (2019) LIMK2-1 is a Hominidae-Specific Isoform of LIMK2 Expressed in Central Nervous System and Associated with Intellectual Disability. Neuroscience, (2019) 399, 199-210.
• Vallée B., Cuberos H., Doudeau M., Godin F., Gosset D., Vourc’h P., Andres C. R. and Bénédetti H. (2018) IMK2-1, a new isoform of Human-LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than its two homologs, LIMK2a/2b.Biochemical Journal (2018) 475 () 3745-3761.
• Deraredj Nadim W., Chaumont-Dubel S., Madouri F., Cobret L., De Tauzia M.-L., Zajdel P., Bénédetti H., Marin P. and Morisset-Lopez S. (2016) A Physical Interaction between Neurofibromin and Serotonin 5-HT6 Receptor Promotes Receptor Constitutive Activity., Proc Natl Acad Sci U S A  113(43) 12310-12315 -doi: 10.1073/pnas.1600914113
• Saurat T., Buron F., Rodriguès N., de Tauzia M.-L., Colliandre L., Bourg S., Bonnet P., Guillaumet G., Akssira M., Corlu A., Guillouzo C., Berthier P., Rio P., Jourdan ML., Bénédetti H. and Routier S. (2014) Design, Synthesis and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/ mTOR Dual Inhibitors. J. Med. Chem., 57, 613-631.
• Vallée B., Doudeau M., Godin F., Gombault A., Tchalikian A., de Tauzia M.-L., and Bénédetti H. (2012) Nf1 RasGAP Inhibition of LIMK2 Mediates a New Cross- Talk between Ras and Rho Pathways. PLOS One, 7, e47283.
• Godin F., Villette S., Vallée B., Doudeau M., Morisset-Lopez S., Ardourel M., Hevor T., Pichon C. and Bénédetti H. (2012) A fraction of neurofibromin interacts with PML bodies in the nucleus of the CCF astrocytoma cell line. BBRC, 418, 689-694.