Biology subjects

Beaumelle, B.

Publications and source records attributed to Beaumelle, B..

4 recordsLinked to original sources

bioRxiv2026

A new HIV-1 latency reversing agent activating HIV-Tat

Despite its efficiency to prevent viral multiplication, antiretroviral therapy does not affect HIV-1 latently-infected cells. These cells do not produce significant amounts of viruses and constitute HIV-1 reservoir. To purge this long-lived viral reservoir, the "shock and kill" strategy relies on the use of latency reversing agents (LRAs) to induce activation of latent cells. All LRAs developed until now target cellular proteins and are therefore not specific for HIV-infected cells. Here we present a new LRA that binds and activates HIV-1 Tat which is the key regulator for viral transcription and latency reversal. This molecule termed D10 was designed to bind to the major groove of the Tat protein, and found to activate Tat transcriptional activity by stabilizing the HIV transcription complex. This LRA induces strong HIV production by latent cell lines and latent cells from people living with HIV-1. On latent cells from PBMCs, D10 is active at [~]50 nM, the concentration required to stabilize HIV transcription complex. D10 is the first Tat activator available and the first LRA that targets an HIV protein.

microbiology↗

bioRxiv2026

HIV-1 Tat protects macrophages from killing by the Exoenzyme U from Pseudomonas aeruginosa

People living with HIV (PLWH) have a higher risk of developing other diseases, such as bacterial pneumonia. While Pseudomonas aeruginosa (PAE) is a common cause of pneumonia in humans, PLWHs are infrequently infected by PAE. The reasons for this relative resistance of PLWH to PAE are not known. The most virulent PAE strains produce ExoU which is a key effector of PAE cytotoxicity. Upon injection into the target cell cytosol by the type III secretion system, ExoU binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. Its phospholipase activity then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is secreted by HIV-infected cells, leading to nanomolar concentrations of Tat in the sera of PLWH, even under antiretroviral therapy. Circulating Tat can be endocytosed by uninfected cells, translocate to the cytosol and bind to PI(4,5)P2 at the plasma membrane. In uninfected cells only, Tat is palmitoylated, enabling Tat to become resident on PI(4,5)P2. We found that Tat can interfere with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from PAE toxicity. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates and their ExoU type III effector. Tat nevertheless enhances the toxicity of ExoU-deficient PAE strains toward macrophages. ImportancePeople living with HIV (PLWH) are at risk of developing bacterial pneumonia. A widespread cause of pneumonia is Pseudomonas aeruginosa (PAE) but, for unknown reasons, PLWHs are infrequently infected by PAE. A key effector of PAE cytotoxicity is ExoU that is injected by PAE into the target cell cytosol, then binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. The potent phospholipase activity of ExoU then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is present in the serum of PLWH. Circulating Tat is endocytosed by cells, translocates to the cytosol and bind to PI(4,5)P2 at the plasma membrane with a very high affinity. This study indicates that Tat interferes with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from ExoU+ PAE. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates.

microbiology↗

bioRxiv2025

Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation

The non-receptor Spleen tyrosine kinase Syk acts downstream of several receptors of the immune system such as the Fc{gamma}R. Syk is composed of a kinase domain and two SH2 domains that interact with the bi- phosphorylated ITAMs motifs of the Fc{gamma}R upon phagocytosis. This results in the activation of Syk by auto- phosphorylation, triggering phosphorylation of several downstream targets in a process that will culminate in F-actin polymerization and phagocytosis of the IgG-opsonized target. We found that Syk is S-acylated upon phagocytosis by macrophages. Palmitoylation is performed on a single Syk-Cys by the protein S-acyl transferase DHHC5 that specifically associates with Syk upon phagocytosis. Syk palmitoylation is required for Syk localization to the phagocytic cup, Syk phosphorylation/activation, Cdc42 recruitment to the cup, F-actin polymerization and phagocytosis. We also observed that another Syk-Cys residue is modified by sulfenylation. Mutation of the sulfenylated Cys that belongs to a redox-motif inactivated the Syk catalytic activity and phagocytosis. We found that Syk desulfenylation occurs during phagocytosis. Molecular dynamics studies indicated that desulfenylation increased the mobility and exposure of a loop within the Syk interdomain B, likely facilitating phosphorylation of key Syk-Tyr residues by upstream effectors such as Src kinases. We thus propose an original updated model for Syk activation during Fc{gamma}R-mediated phagocytosis that involves both Syk palmitoylation and desulfenylation.

cell biology↗

bioRxiv2022

A tripartite complex HIV-1 Tat-cyclophilin A-capsid protein enables Tat encapsidation that is required for HIV-1 infectivity

HIV-1 Tat is a key viral protein that stimulates several steps of viral gene expression. Tat is especially required for the transcription of viral genes but it is still not clear if and how Tat is incorporated into HIV-1 virions. Cyclophilin A (CypA) is a prolylisomerase that binds to HIV-1 capsid protein (CA) and is thereby encapsidated. Here we found that a Tat-CypA-CA tripartite complex assembles in HIV-1 infected cells. Biochemical and biophysical studies showed that high affinity interactions drive the assembly of this complex. Virions devoid of encapsidated Tat showed a 5-10 fold decrease in HIV-infectivity and, conversely, encapsidating Tat into {Delta}Tat viruses greatly enhanced infectivity. The absence of encapsidated Tat decreases the efficiency of retrotranscription by [~]50% and transcription by 99%. We thus identified a Tat-CypA-CA complex that enables Tat encapsidation and showed that encapsidated Tat is required to initiate robust HIV-1 infection and viral production.

microbiology↗