Biology subjects

Lemasson, M.

Publications and source records attributed to Lemasson, M..

4 recordsLinked to original sources

bioRxiv2026

Fluoxetine-induced neurogenesis and chronic antidepressant effects requires the dopamine D2 receptor.

Major depressive disorder (MDD) is a common psychiatric illness with a high proportion of patients being nonresponsive to therapy. Selective serotonin reuptake inhibitors (SSRI) are widely prescribed for treating depression. Chronic SSRI administration is needed for therapeutic effects, a process implicating in part, increased neurogenesis in the hippocampus. Recent genome wide association studies (GWAS) identified the DrD2 locus, which encodes the dopamine D2 receptor (D2R) as a major risk factor in MDD. Here we demonstrate that behavioural effects associated with chronic administration of the SSRI drug fluoxetine and its accompanying neurogenic effects require D2R. Administration of fluoxetine to congenital D2R-knockout mice, or co-administration of the antidepressant with the antipsychotic D2R antagonist drug haloperidol prevented the neurogenic effects of fluoxetine. Furthermore, while acute behavioural responses to fluoxetine did not require D2R, this receptor was essential for the behavioural effects of chronic fluoxetine. The neurogenic impact of chronic fluoxetine was further associated with beta-arrestin 2-mediated signalling and the hippocampal regulation of the pro-neurogenic factor BDNF. These results support a role of D2R in regulating the therapeutically relevant chronic effects of fluoxetine on mood, BDNF signalling, and associated hippocampal neurogenesis. Furthermore, our findings suggest an unappreciated interaction between genetic risk for MDD and treatment responsiveness as well as a negative interaction between SSRIs and antipsychotic drugs in the regulation of hippocampal neurogenesis.

neuroscience↗

bioRxiv2023

Tick-borne flavivirus NS5 antagonizes interferon signaling by inhibiting the catalytic activity of TYK2

The mechanisms utilized by different flaviviruses to evade antiviral functions of interferons are varied and incompletely understood. Using virological approaches, biochemical assays and mass spectrometry analysis, we report here that the NS5 protein of tick-borne encephalitis virus (TBEV) and Louping Ill virus (LIV), two related tick-borne flaviviruses, antagonize JAK-STAT signaling through interactions with tyrosine kinase 2 (TYK2). Co-immunoprecipitation (co-IP) experiments, yeast gap-repair assays, computational protein-protein docking and functional studies identified a stretch of 10 residues of the RNA dependent RNA polymerase domain of tick-borne flavivirus NS5, but not mosquito-borne NS5, that is critical for interaction with the TYK2 kinase domain. Additional co-IP assays performed with several TYK2 orthologs revealed that the interaction was conserved across mammal species. In vitro kinase assays showed that TBEV and LIV NS5 reduced the catalytic activity of TYK2. Our results thus illustrate a novel mechanism by which viruses suppress the interferon response. TeaserInhibition of the catalytic activity of a key kinase of the JAK/STAT pathway by a viral protein

microbiology↗

bioRxiv2022

Integrated protein-protein interaction and RNA interference screens reveal novel restriction and dependency factors for a tick-borne flavivirus in its human host

In Europe, tick-borne encephalitis virus (TBEV) is responsible for severe neurological disease in humans. Like other viruses, TBEV is an obligate intracellular life form whose survival requires subversion of metabolic processes and evasion of anti-viral pathways. This feat is achieved in no small part by binary interactions between dedicated viral proteins and host proteins. Such protein-protein interactions (PPI) constitute molecular determinants of critical pathobiologic traits of viruses, including host-range, zoonotic potential and virulence, and represent realistic targets for anti-viral therapies. To shed light on the pathobiology of TBEV in human, we have resolved the network of PPI established with its human host by interaction proteomics. A high-throughput screen for virus-host PPI was performed involving the complete set of open reading frames of TBEV and the cDNA libraries of Homo sapiens, by means of yeast two-hybrid methodology. We have discovered a large set of virus-host protein-protein interactions concerning 42 different human proteins directly interacting with nine viral proteins. Many of these human interactors have never been linked in the literature to viral infection. The functional significance of the host interactors in viral infection as viral dependency or restriction factors was then characterized in vitro by RNA interference, and their function inferred by bioinformatic analysis. Approximately 40% of the identified human proteins have a significative impact on TBEV viral replication. These are engaged in many biological processes, whose involvement in viral infection is expected for many, but enigmatic for some. Further work will be necessary to gain molecular understanding of how these biological processes support or restrict TBEV replication, and whether they constitute viral vulnerabilities that can be exploited therapeutically.

microbiology↗

bioRxiv2019

Hepatitis C virus regulates its replication by maturing miR-122 through Akt-dependent phosphorylation of KSRP

The liver-specific micro-RNA-122 (miR-122) is required for the replication of hepatitis C virus (HCV). The direct interaction between miR-122 and the 5 untranslated region of the HCV genome promotes viral replication and protects HCV RNA from degradation. Because HCV RNA is its own substrate for replication, infected cells are submitted to the sequestration of increasing levels of miR-122 and to global de-repression of host miR-122 mRNA targets. Whether and how HCV regulates miR-122 maturation to create an environment favorable to its replication remains unexplored. We discovered that Akt-dependent phosphorylation of KSRP host protein at Serine residue 193 is essential for miR-122 maturation in hepatocytes. Moreover, we showed the existence of a reciprocal regulation loop where HCV replication can modulate the proviral effect mediated by KSRP-dependent maturation of miR-122. These data support a mechanism by which HCV regulates the expression of miR-122 by hijacking KSRP, thereby fueling its own replication.

microbiology↗