Biology subjects

Adoro, S.

Publications and source records attributed to Adoro, S..

3 recordsLinked to original sources

bioRxiv2025

Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome, yet strategies to enhance lymphocyte regeneration are limited. We studied the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We revealed that PERK activation is a prominent feature of BM endothelium in leukemia patients and is a hallmark response in mouse BM following ionizing irradiation. Ablating endothelial Perk boosted Notch ligand DLL4 expression and promoted DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis shows that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment and niche cytokine production. NOTCH3 is critical for the upregulation of IL7 following irradiation and for supporting the expansion of lymphoid progenitors in mesenchymal sphere cultures. These findings not only unveil a previously unrecognized ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising therapeutic strategy to improve immune recovery after myeloablative transplantation. SummaryZou et al unravel that the adaptive ER stress response in bone marrow blood vessels restricts the post-transplant regeneration of immune progenitor cells by attenuating the expression of Notch ligand DLL4. Targeting ER stress sensor PERK can accelerate immune recovery after transplantation by enhancing DLL4-NOTCH3 signaling and IL7 cytokine production.

cell biology↗

bioRxiv2024

The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription

Oncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notably MYC. Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1 in vivo. Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/577409v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@191e10dorg.highwire.dtl.DTLVardef@4e5093org.highwire.dtl.DTLVardef@18c0a08org.highwire.dtl.DTLVardef@e6a887_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcription C_LIO_LICHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genes C_LIO_LIP300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5 C_LIO_LICHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiation in vivo C_LI

cancer biology↗

bioRxiv2021

Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β-Selection

Signals from the pre-T cell receptor and Notch coordinately instruct {beta}-selection of CD4-CD8- double negative (DN) thymocytes to generate {beta} T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre- selection TCR repertoire given the considerable translational activity imposed by {beta}-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during {beta}-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired {beta} T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l- deficient thymocytes. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

immunology↗