Mesnard, J.-M. | bioRxiv Science

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

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↗