Biology subjects

Marty, L.

Publications and source records attributed to Marty, L..

5 recordsLinked to original sources

bioRxiv2026

Transcriptional rewiring of NF-κB by HBZ and Fra-2 drives inflammatory chemoresistance in Tax-negative adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive HTLV-1-associated malignancy with poor responses to chemotherapy. Although constitutive NF-kB activation is a hallmark of ATL, its persistence in tax-negative (Type I) ATL, where Tax is irreversibly silenced, remains unresolved. Here, we identify Fra-2 as a coactivator of NF-kB p65 that redirects p65's transcriptional activity toward inflammatory genes. Mechanistically, Fra-2 interacts with the Rel homology domain of p65 via its bZIP domain, enhancing p65 DNA-binding activity without altering nuclear localization. The HTLV-1 antisense protein HBZ disrupts Fra-2/JunD AP-1 complexes while stabilizing Fra-2/p65, as shown by co-immunoprecipitation, BiFC, and PICO assays. This rewiring selectively enhances NF-kB-dependent transcription of IL-1b, which is elevated in ATL patient sera and cells independently of proviral load. Chromatin immunoprecipitation revealed Fra-2 recruitment to NF-kB response elements in the IL1b promoter, an effect amplified by HBZ. Pharmacological inhibition of IL-1 signaling with anakinra or anti-IL-1b antibodies restored doxorubicin sensitivity in primary ATL cells. Together, these findings establish the Fra-2-NF-kB-IL-1b axis as a driver of chemoresistance in tax-negative ATL and a therapeutically targetable vulnerability.

cancer biology↗

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

Antagonistic regulation of HBZ splicing by hnRNPA1 and hnRNPH1 drives HTLV-1 leukemogenesis.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive leukemia driven by Human T-cell Leukemia Virus type 1 (HTLV-1) and remains largely refractory to current therapies. Although hbz is the only viral transcript consistently expressed in acute ATL, the extent to which its alternative splicing shapes disease biology remains unknown. Here, we demonstrate that the splicing of hbz plays a key role in driving cancer development in ATL. Quantitative analyses in HTLV-1-infected cell lines and primary samples revealed a striking enrichment of the spliced isoform HBZ_SP1 (over 200-fold) in CD4 T cells from ATL patients, whereas the unspliced transcript (usHBZ) predominates in CD8 T cells. Despite robust transcription, the usHBZ protein was undetectable, whereas HBZ_SP1 accumulated rapidly, identifying it as the main isoform in CD4 T cells from ATL patients. Furthermore, only HBZ_SP1 drove cellular transformation and conferred marked resistance to chemotherapeutic stress. Mechanistically, we identify a splicing regulatory axis centered on hnRNPA1 and hnRNPH1. Both proteins bind hbz pre-mRNA, but exert opposing effects: hnRNPA1 represses splicing, whereas hnRNPH1 promotes production of the oncogenic HBZ_SP1 isoform. Perturbation of this balance reprograms HBZ isoform expression and alters leukemic cell fitness. Collectively, our findings establish that HBZ inhibits hnRNPA1 transcription, therefore allowing HTLV-1 to hijack host RNA splicing and to generate an oncogenic isoform that drives transformation and chemoresistance. These results uncover a previously unrecognized post-transcriptional mechanism of viral leukemogenesis and position HBZ splicing and its regulators as therapeutic targets in ATL. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/739521v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1298adorg.highwire.dtl.DTLVardef@e5a7beorg.highwire.dtl.DTLVardef@167d576org.highwire.dtl.DTLVardef@1ef68f6_HPS_FORMAT_FIGEXP M_FIG C_FIG Mechanistic model of HBZ splicing regulation. This simplified graphical abstract summarizes the highlights of our study. Here, we hypothesize that in CD4+ T cells infected by HTLV-1, transcription and splicing reprogramming lead to a preferential expression of the HBZ_SP1 oncogenic isoform, specifically due to an overexpression of the splicing activator hnRNP H1and repression of hnRNP A1 by HBZ itself via C/EBP. HBZ_SP1 is consistently expressed and then drives cell transformation and chemoresistance. In contrast, in CD8+ T cells infected with HTLV-1, the HBZ-mediated downregulation of hnRNP A1 is overcome, leading to inhibition of HBZ splicing and increased expression of the less oncogenic isoform usHBZ.

molecular 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↗

bioRxiv2019

Arabidopsis glutathione reductase 2 is indispensable in plastids, while mitochondrial glutathione is safeguarded by additional reduction and transport systems

O_LIA highly negative glutathione redox potential (EGSH) is maintained in the cytosol, plastids and mitochondria of plant cells to support fundamental processes, including antioxidant defence, redox regulation and iron-sulfur cluster biogenesis. Out of two glutathione reductase (GR) proteins in Arabidopsis, GR2 is predicted to be dual-targeted to plastids and mitochondria, but its differential roles in these organelles remain unclear.\nC_LIO_LIWe dissected the role of GR2 in organelle glutathione redox homeostasis and plant development using a combination of genetic complementation and stacked mutants, biochemical activity studies, immunogold labelling and in vivo biosensing.\nC_LIO_LIOur data demonstrate that GR2 is dual-targeted to plastids and mitochondria, but embryo lethality of gr2 null mutants is caused specifically in plastids. Whereas lack of mitochondrial GR2 leads to a partially oxidised glutathione pool in the matrix, the ABC transporter ATM3 and the mitochondrial thioredoxin system provide functional backup and maintain plant viability.\nC_LIO_LIWe identify GR2 as essential in the plastid stroma, where it counters GSSG accumulation and developmental arrest. By contrast a functional triad of GR2, ATM3 and the thioredoxin system in the mitochondria provides resilience to excessive glutathione oxidation.\nC_LI

plant biology↗