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Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI176093.
Abstract
Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small molecule activators of PP2A (SMAPs) to explore the role of B56-PP2A(s) in 4E-BP regulation and the potential of B56-PP2A activation for restoring translational control in tumors. SMAP treatment promoted PP2A-dependent hypophosphorylation of 4E-BP1/2, supporting a role for B56-PP2As (e.g., B56α-PP2A) as 4E-BP phosphatases. Unexpectedly, SMAPs induced transcriptional upregulation of 4E-BP1 through a B56 PP2A→TFE3/TFEB→ATF4 axis. Cap-binding and co-immunoprecipitation assays showed that B56-PP2A(s) activation blocks assembly of the eIF4F translation initiation complex, and cap-dependent translation assays confirmed the translation inhibitory effects of SMAPs. Thus, B56-PP2A(s) orchestrate a translation repressive program involving transcriptional induction and activation of 4E-BP1. Notably, SMAPs promoted 4E-BP1-dependent apoptosis in tumor cells and potentiated 4E-BP1 function in the presence of ERK or mTOR inhibitors, agents that rely on inhibition of eIF4E-dependent translation for antitumor activity. These findings, combined with the ability of SMAPs to regulate 4E-BP1 in vivo, highlight the potential of PP2A activators for cancer therapy and overcoming therapy resistance.
Authors
Michelle A. Lum, Kayla A. Jonas, Shreya Parmar, Adrian R. Black, Caitlin M. O'Connor, Stephanie Dobersch, Naomi Yamamoto, Tess M. Robertson, Aidan Schutter, Miranda Giambi, Rita A. Avelar, Analisa DiFeo, Nicholas T. Woods, Sita Kugel, Goutham Narla, Jennifer D. Black
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI182584.
Abstract
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) that begins in the first year of life. While most cases of DS are caused by variants in SCN1A, variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are also linked to DS or to the more severe early infantile DEE. Both disorders fall under the OMIM term DEE52. Scn1b null mice model DEE52, with spontaneous generalized seizures and death in 100% of animals in the third postnatal week. Scn1b null cortical parvalbumin-positive interneurons and pyramidal neurons are hypoexcitable. The goal of this study was to develop a proof-of-principle gene replacement strategy for DEE52. We tested an adeno-associated viral vector encoding β1 subunit cDNA (AAV-Navβ1) in Scn1b null mice. We demonstrated that AAV-Navβ1 drives β1 protein expression in excitatory and inhibitory neurons in mouse brain. Bilateral intracerebroventricular administration of AAV-Navβ1 in Scn1b null mice at postnatal day (P) 2, but not at P10, reduced spontaneous seizure severity and duration, prolonged life span, prevented hyperthermia-induced seizures, and restored cortical neuron excitability. AAV-Navβ1 administration to WT mice resulted in β1 overexpression in brain but no obvious adverse effects. This work lays the foundation for future development of a gene therapeutic strategy for SCN1B-linked DEE patients.
Authors
Chunling Chen, Yukun Yuan, Heather A. O'Malley, Robert Duba-Kiss, Yan Chen, Karl Habig, Yosuke Niibori, Samantha L. Hodges, David R. Hampson, Lori L. Isom
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180981.
Abstract
Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified three young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous one base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.
Authors
Alexandrine Garrigue, Laëtitia Kermasson, Sandrine Susini, Ingrid Fert, Christopher B. Mahony, Hanem Sadek, Sonia Luce, Myriam Chouteau, Marina Cavazzana, Emmanuelle Six, Marie-Caroline Le Bousse-Kerdilès, Adrienne Anginot, Jean-Baptiste Souraud, Valérie Cormier-Daire, Marjolaine Willems, Anne Sirvent, Jennifer Russello, Isabelle Callebaut, Isabelle André, Julien Y. Bertrand, Chantal Lagresle-Peyrou, Patrick Revy
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186388.
Abstract
BACKGROUND. B7-H3 or CD276 is notably overexpressed in various malignant tumor cells in humans, with extremely high expression rates. The development of a radiotracer that targets B7-H3 may provide a universal tumor-specific imaging agent and allow the noninvasive assessment of the whole-body distribution of B7-H3-expressing lesions. METHODS. We enhanced and optimized the structure of an affibody (ABY) that targets B7-H3 to create the radiolabeled radiotracer [68Ga]Ga-B7H3-BCH, and then, we conducted both foundational experiments and clinical translational studies. RESULTS. [68Ga]Ga-B7H3-BCH exhibited high affinity (Kd = 4.5 nM), and it was taken up in large amounts by B7-H3-transfected cells (A549CD276 and H1975CD276 cells); these phenomena were inhibited by unlabeled precursors. Moreover, PET imaging of multiple xenograft models revealed extensive [68Ga]Ga-B7H3-BCH uptake by tumors. In a clinical study including 20 patients with malignant tumors, the [68Ga]Ga-B7H3-BCH signal aggregated in both primary and metastatic lesions, surpassing 18F-FDG in overall diagnostic efficacy for tumors (85.0% vs 81.7%), including differentiated hepatocellular and metastatic gastric cancers. A strong correlation between B7-H3 expression and [68Ga]Ga-B7H3-BCH uptake in tumors was observed, and B7-H3 expression was detected with 84.38% sensitivity and 100% specificity when an SUVmax of 3.85 was set as the cutoff value. Additionally, B7-H3-specific PET imaging is expected to predict B7H3 expression levels in tumor cells, intratumoral stroma and peritumoral tissues. CONCLUSION. In summary, [68Ga]Ga-B7H3-BCH has potential for the noninvasive identification of B7H3 expression in systemic lesions in patients with malignant tumors. This agent has prospects for improving pretreatment evaluation, predicting therapeutic responses, and monitoring resistance to therapy in patients with malignancies. TRIAL REGISTRATION. ClinicalTrials.gov NCT06454955. FUNDING. This research was financially supported by the Natural Science Foundation of Beijing Municipality (No. 7242266), the National Natural Science Foundation of China (No. 82202201), and the Young Elite Scientists Sponsorship Program by CAST (No. YESS20220230).
Authors
Lei Xia, Yan Wu, Yanan Ren, Zhen Wang, Nina Zhou, Wenyuan Zhou, Lixin Zhou, Ling Jia, Chengxue He, Xiangxi Meng, Hua Zhu, Zhi Yang
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185146.
Abstract
The role of macrophages remains incompletely understood in kidney injury and repair. Their plasticity offers an opportunity to polarize them towards mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney macrophages augmented their AIF-1 expression after injury. Aif1 genetic deletion led to macrophage polarization towards a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of anti-inflammatory and pro-regenerative markers leading to a reduction in cell death and increase in proliferation of kidney tubular epithelial cells following ischemic reperfusion injury. Adoptive transfer of Aif1-/- macrophages to Aif1+/+ mice conferred protection against ischemia reperfusion injury. Conversely, depletion of macrophages reversed the tissue-reparative effects in Aif1-/- mice. We further demonstrated an increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a macrophage marker of renal inflammation, and its targeting uncouples macrophage reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.
Authors
Irma Husain, Holly Shah, Collin Z. Jordan, Naveen R. Natesh, Olivia K. Fay, Yanting Chen, Jamie R. Privratsky, Hiroki Kitai, Tomokazu Souma, Shyni Varghese, David N. Howell, Edward B. Thorp, Xunrong Luo
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI182125.
Abstract
The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared to female mice. Sex-mismatched co-culture and BM transplantation showed that the male BM niche provided superior support for in vitro colony formation and in vivo hematopoietic engraftment. The co-transplantation of male stromal cells significantly enhanced engraftment in female recipients. Single-cell RNA sequencing revealed that the lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs led to the increased expression of Cxcl12. In MSC-specific Kdm5c knockout mouse model, the reduction of KDM5C in female MSCs enhanced MSC quantity and function, ultimately improving engraftment to the male level. Kdm5c thus plays a role in driving sexual dimorphism in the BM niche and hematopoietic regeneration. Our study unveils a sex-dependent mechanism governing BM niche regulation and its impact on hematopoietic engraftment. The finding offers potential implications for enhancing BM transplantation efficacy in clinical settings by harnessing the resource of male MSCs or targeting Kdm5c.
Authors
Xiaojing Cui, Liming Hou, Bowen Yan, Jinpeng Liu, Cuiping Zhang, Pinpin Sui, Sheng Tong, Larry Luchsinger, Avital Mendelson, Daohong Zhou, Feng-chun Yang, Hui zhong, Ying Liang
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188016.
Abstract
Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that co-expressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (CTL) over-expressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only Intraepithelial Lymphocytes-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6h post-infection while at 24h post-infection AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24h post-infection only AM from resisters displayed a significant upregulation of MICA transcripts which encode an activating ligand for poly-CTL. These results suggest that poly-CTL and AM mediate the resister phenotype in PWH.
Authors
Monica Dallmann-Sauer, Vinicius M. Fava, Stephanus T. Malherbe, Candice E. MacDonald, Marianna Orlova, Elouise E. Kroon, Aurélie Cobat, Stéphanie Boisson-Dupuis, Eileen G. Hoal, Laurent Abel, Marlo Möller, Jean-Laurent Casanova, Gerhard Walzl, Nelita Du Plessis, Erwin Schurr
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185426.
Abstract
Background: Myotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness. Methods: Total RNA sequencing of tibialis anterior biopsies from 58 DM1 participants and 33 unaffected/disease controls was used to evaluate RNA splicing events across the disease spectrum. Targeted RNA sequencing was used to derive the SI from biopsies collected at baseline (n = 52) or a 3-month (n = 37) follow-up visit along with clinical measures of muscle performance. Results: The SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk (Pearson r = -0.719 and -0.680, respectively). The SI was relatively stable over 3-months (ICC = 0.863). Latent-class analysis identified three DM1 subgroups stratified by baseline SI (SIMild, SIModerate, SISevere); SIModerate individuals had a significant increase in the SI over 3-months. Multiple linear regression modeling revealed that baseline ADF and SI were predictive of strength at 3-months (adjusted R² = 0.830). Conclusion: The SI is a reliable biomarker that captures associations of RNA mis-splicing with physical strength and mobility and has prognostic utility to predict future function, establishing it as a potential biomarker for assessment of therapeutic target engagement. Trial Registration: NCT03981575 Funding: FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.
Authors
Marina Provenzano, Kobe Ikegami, Kameron Bates, Alison Gaynor, Julia M. Hartman, Aileen S. Jones, Amanda Butler, Kiera N. Berggren, Jeanne Dekdebrun, Man Hung, Dana M. Lapato, Michael Kiefer, Charles A. Thornton, Nicholas E. Johnson, Melissa A. Hale
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186769.
Abstract
Authors
Felicitas E. Hengel, Silke Dehde, Oliver Kretz, Jonas Engesser, Tom Zimmermann, Tobias B. Huber, Nicola M. Tomas
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI171077.
Abstract
Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge. Here we report that genetic or pharmacologic inhibition of the PDGF-CC/PDGFRα pathway, which has previously been implicated in stroke pathology, significantly reduced myofibroblast expansion in the border of the fibrotic scar and improved outcome in a sensory-motor integration test after experimental ischemic stroke. This was supported by gene expression analyses of cerebrovascular fragments, showing upregulation of pro-fibrotic/pro-inflammatory genes, including genes of the TGFβ pathway, after ischemic stroke or intracerebroventricular injection of active PDGF-CC. Further, longitudinal intravital two-photon imaging revealed that inhibition of PDGFRα dampened the bi-phasic pattern of stroke-induced vascular leakage and enhanced vascular perfusion in the ischemic lesion. Importantly, we found efficacy of PDGFRα inhibition on functional recovery when initiated 24 hours after ischemic stroke. Our data implicate the PDGF-CC/PDGFRα pathway as a crucial mediator modulating post-stroke pathology and suggest a post-acute treatment opportunity for ischemic stroke patients targeting myofibroblast expansion to foster long-term CNS repair.
Authors
Jil Protzmann, Manuel Zeitelhofer, Christina Stefanitsch, Daniel Torrente, Milena Z. Adzemovic, Kirils Matjunins, Stella J.I. Randel, Sebastian A. Lewandowski, Lars Muhl, Ulf Eriksson, Ingrid Nilsson, Enming J. Su, Daniel A. Lawrence, Linda Fredriksson
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