Cell biology
Abstract
Splenic myelopoiesis supplies immunosuppressive myeloid cells in cancer, yet its local regulation remains unclear. Here we identify a self-amplifying circuit between neutrophils and hematopoietic stem and progenitor cells (HSPCs) that sustains splenic myelopoiesis. Tumor-associated neutrophils produced reactive oxygen species (ROS) and created an oxidatively stressed milieu in the spleen, which activated FOXO1 in neighboring HSPCs and drove DRP1-mediated mitochondrial fission, reprogramming HSPCs toward myeloid-biased expansion and immunosuppressive output. Progeny neutrophils reinforced splenic oxidative stress and perpetuated this loop. Genetic ablation of Cybb or spleen-targeted ROS scavenging inhibited FOXO1 activation and preserved fused mitochondria morphology in HSPCs. Consistently, blockade of FOXO1 or DRP1 prevented mitochondrial fission and reduced ROS-producing myeloid cell generation. Such interventions reduced splenic myelopoiesis, curtailed the production of suppressive myeloid cells in the spleen and their infiltration into tumors, and enhanced cytotoxic T cell activity, thereby restoring antitumor immunity and restraining tumor progression. Analyses of spleen samples from cancer patients, together with cord-blood HSPC and neutrophil co-culture experiments, support the human relevance of this neutrophil–ROS–HSPC axis. These findings reveal a self-propagating neutrophil–HSPC feedback circuit that locally sustains tumor-promoting splenic myelopoiesis and provide a rationale for targeting neutrophil-to-progenitor signaling to normalize antitumor immunity.
Authors
Lan Zhu, Shufeng Luo, Qiaomin Hua, Chang-An Zhao, Huiling Lin, Mingyu Liu, Lingyan Zhu, Jiabin Zheng, Huolun Feng, Yong Li, Chong Wu, Limin Zheng
Abstract
During organogenesis, stem cells undergo cellular and metabolic remodelling, facilitated by autophagy-mediated turnover of organelles. Autophagy impairment has been linked to human diseases, including neurodevelopmental disorders associated with disrupted neural stem/precursor cell (NPC) homeostasis, but the underlying mechanisms and pathogenic processes governing these connections remain poorly understood. Here, we report three de novo variants of uncertain significance (p.Gly223Asp, p.Gly889Glu, p.Met978Val) in the deubiquitinase USP15 in human probands with diverse clinical features, including a spectrum of brain malformations and metabolic phenotypes. Proband variants differentially altered USP15 activity and nucleocytoplasmic localization. USP15 showed dynamic localization in NPCs of embryonic mouse cerebral cortex. Using a knock-in mouse model carrying the p.Met978Val variant, we showed that aberrant cytoplasmic accumulation of USP15, but not its loss-of-function, impaired NPC self-renewal and differentiation, leading to reduced neuronal output and enlarged lateral ventricles. Mechanistically, USP15 deubiquitinated autophagy regulator ATG16L1, impeded its normal turnover, and impaired autophagy. Concurrently, lipid droplet mobilization and mitochondrial dynamics were attenuated. Reestablishing the ubiquitination-deubiquitination balance restored autophagy activity and normal neurogenesis. Our findings suggest that nucleocytoplasmic shuttling of USP15 creates a switch-like autophagy signal controlling NPC homeostasis, and its disruption may contribute to the pathogenesis of complex neurodevelopmental conditions.
Authors
Kaylan M.L. Burns, Mashiat Zaman, Daniel Young, Michelle Hua, Yu-Yun Gao, Yvonne Yan Yan Or, Farzaneh Nobakht, Bryn D. Webb, Julie A. Jurgens, Francis Ramond, Xing-Chang Wei, Caroline D. Robson, Alistair T. Pagnamenta, Marvel Megaly, Belal Tafech, Antoine Dufour, Timothy E. Shutt, Ping Yee Billie Au, Guang Yang
Abstract
γ-Secretase is a transmembrane protease complex that cleaves multiple type I transmembrane proteins, including amyloid precursor protein and neurogenic locus notch homolog protein (NOTCH). Although numerous γ-secretase inhibitors and modulators targeting Notch-dependent cancers have been developed in recent decades, their clinical translation has been hampered by low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we identified dedicator of cytokinesis protein 2 (DOCK2) as an interactor of the γ-secretase subunit nicastrin (NCSTN). We further demonstrate that DOCK2 regulates mannosylation of NCSTN N-glycans, which in turn modulates γ-secretase activity toward NOTCH receptors. Both genetic depletion of DOCK2 and pharmacological inhibition of NCSTN mannosylation with kifunensine attenuated Notch-dependent leukemia progression in vivo. Collectively, these findings uncover a regulatory mechanism underlying substrate-specific activation of γ-secretase and suggest a promising therapeutic strategy for Notch-related diseases.
Authors
Hua Jiang, Weixiang Bian, Yanjun Cao, Zhuo Zhang, Yijia Chen, Yue Sui, Hongqiang Qin, Xu Li
Abstract
Distress sharing within an ingroup instinctively motivates caregiving-like prosocial behavior in social animals and humans, yet how aversive social stimuli paradoxically trigger such behavior remains unclear. Here, we show that stress-state matching in observer mice elicits caregiving-like behaviors (allogrooming and injury-targeted allolicking) toward cagemates in pain, resulting in synchronized social buffering. Importantly, we identify that the excitation of vasopressin receptor 1a–expressing (V1aR-expressing) neurons in the central medial amygdala (CeM) underlies both emotional-state matching and subsequent allogrooming/allolicking. This excitation is accomplished by arginine vasopressin (AVP) release from presynaptic terminals of the hypothalamic paraventricular nucleus (PVN) to act specifically on postsynaptic V1aR in the CeM. The CeMV1aR neurons then project to the ventral tegmental area (VTA) to drive caregiving-like actions through positive reinforcement, manifested as prosocial preference and recurrent allogrooming/allolicking, and to produce anxiolysis in the caregiver. Collectively, we unravel a dedicated trisynaptic PVNAVP-CeMV1aR-VTA circuit driving and gating caregiving-like behaviors and advance the mechanistic understanding of AVP-V1aR signaling in prosociality.
Authors
Kai-Wen Geng, Rui-Rui Wang, Yan Yang, Yan Wang, Ting He, Chun-Li Li, Chong-Shun Xu, Jun Chen
Abstract
Vascular endothelial cells (ECs) encode a homeostatic fluid shear stress (FSS) set point that is essential for vascular stability. Deviations above or below this threshold trigger adaptive remodeling to restore physiological shear levels. Disruption of this control mechanism leads to enlarged arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia, a vascular disorder caused by heterozygous loss-of-function (LOF) mutation in ALK1, ENG, or SMAD4. Mechanistically, Smad4-deficient ECs are reset to a lower FSS set point value, resulting in AVMs that show characteristics of high-FSS remodeling with elevated KLF4 and high activation of the downstream Akt. Here, we investigated the KLF4/Akt upstream mechanisms by which SMAD4 sets the physiological FSS set point. We identified the receptor tyrosine kinase c-KIT as a component and regulator of the junctional mechanosensory receptor complex, which is highly upregulated in murine and human AVMs. SMAD4 restrains flow signaling by limiting c-KIT–dependent ERK5 activation and KLF4 induction. Thus, SMAD4 LOF leads to sustained c-KIT engagement in the sensory junctional apparatus, driving enhanced and prolonged activation of the ERK5/KLF4/Akt signaling axis. These results show that Smad4-LOF mutations induce malformations by disabling a key homeostatic mechanism and identify c-KIT as a potentially previously unrecognized therapeutic target.
Authors
Johannes Gahn, Fan Wu, Qing Zhang, Yuxi Di, Tanmaya Behera, Yonggang Ren, Zohrah Hashemi, Kuheli Banerjee, Julio Cordero, Claudia Gherman, Kornelia Andorfer, Caroline T. Seebauer, Fatemeh Mirzapour-Shafiyi, Gergana Dobreva, Martin A. Schwartz, Roxana Ola
Abstract
Recent studies have revealed that, beyond their classical role in platelet production, megakaryocytes (MKs) express immune-related genes and exert important immunoregulatory functions. However, it remains unclear whether these functions arise from a single versatile population or from distinct specialized subtypes, and how such subtypes influence infection and inflammation. Here, we identified three specialized immune MK subtypes (imm-MKs)—macrophage-like MKs (Mac-MKs), neutrophil-like MKs (Neu-MKs), and antigen-presenting MKs (APC-MKs)—each defined by distinct transcriptional programs and regulatory networks, with comparable heterogeneity observed in human MKs. Developmental analyses showed that MK immune-related programs increased with maturation and that immune MK subtypes exhibited distinct tissue- and stage-dependent patterns. Functionally, MK subtypes exhibited phase-specific responses during bacterial pneumonia: early infection preferentially induced Mac-MKs and Neu-MKs, which contributed to pulmonary inflammation, whereas during the post-peak acute-to-early-recovery stage, APC-MKs supported a Treg-associated regulatory program that contributed to pulmonary inflammatory control. This MK–Treg axis uncovers a previously unrecognized mechanism of hematopoietic–immune crosstalk. Collectively, our study delineates organ- and stage-specific immune specialization of MKs and identifies immune MK subtypes as dynamic contributors to phase-specific inflammatory and Treg-linked regulatory programs during development and infection.
Authors
Huizhen He, Yezi Ma, Yifei Cai, xiaoyuan chen, Tianran Cheng, Ziqi Huo, Sibei Guo, Meijuan Xia, Dan Feng, Minmin Li, Jingjing Zhao, Nananan Zhao, Pei Su, Wen Zhou, Fei Wang, Cuicui Liu, Hongtao Wang, Jiaxi Zhou
Abstract
Oil-producing sebaceous glands (SGs), attached to the upper/ middle portion of hair follicles, are indispensable for maintaining skin hydration, and their dysfunction leads to dry skin. However, the molecular mechanisms underlying regulation of SG stem cells remain largely unknown. We identified transcription factor KROX20 as a marker of SG stem cells that sustains their stemness throughout SG morphogenesis and homeostasis. We developed an inducible mouse model in which ablation of KROX20-positive cells causes SG loss and rapidly and robustly induces dry, flaky, alopecia symptoms following induction. This model, termed Xeroflacia (Xero = xerosis, fla = flaky, cia = alopecia), provides a tool for studying the biology of dry skin. Furthermore, we found that KROX20 directly regulates Notch1 transcription to orchestrate the balance between SG stem cell self-renewal and differentiation. Small molecule drug modulation of Notch1 signaling to activate or inhibit the pathway enabled us to regulate SG differentiation to maintain skin oil levels, providing a proof-of-principle that other signaling pathways downstream of Krox20 could be potential therapeutic targets for sebaceous gland-related diseases.
Authors
Yumeng Zhang, Pernelle Pulh, Michelle F. Pan, Yi He, Juanzhu Yan, Annie Li, Renée M. McKay, Lu Q. Le
Abstract
Advanced prostate cancer has increasingly developed a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease. The molecular mechanisms remain unclear and no effective therapies currently exist. We report that tryptophan hydroxylase 1 (TPH1), the enzyme responsible for peripheral serotonin biosynthesis — a neurotransmitter enriched in neuroendocrine tumors and a classical neuroendocrine biomarker — was upregulated in both de novo and therapy-induced human NEPC. TPH1 upregulation was necessary and sufficient for neuroendocrine differentiation and the NEPC phenotype through its enzymatic activity. Silencing TPH1 suppressed neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and NEPC tumor xenograft growth. Mechanistically, TPH1 activated mTOR via intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, which triggered the induction of FOXM1 and E2F1 to drive NEPC differentiation and growth. Importantly, pharmacological inhibition of TPH1 using the clinically available inhibitor LX1606 effectively restricted growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Collectively, these findings characterize TPH1’s contribution to NEPC and suggest TPH1 as a potential therapeutic target.
Authors
Jing Wei, Jing Wang, Jingrui Chen, Michelle Zhang, Chia-Hui Chen, Tianjie Pu, Alivia O'Brien, Sephtis Hargrove, Eva Corey, Tzu-Ping Lin, Allen C. Gao, Boyang Jason Wu
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.
Authors
Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang
Abstract
Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.
Authors
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)