Despite being the first homolog of the bacterial RecQ helicase to be identified in humans the function of RECQL1 remains poorly characterised. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here we identify two families with a novel genome instability disorder, named RECON (RECql ONe) Syndrome caused by biallelic mutations in the RECQL gene. The affected individuals exhibit short stature, progeroid facial features, a hypoplastic nose, xeroderma and skin photosensitivity. Affected individuals were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser) located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase and fork restoration activity, whilst its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.
Bassam Abu-Libdeh, Satpal S. Jhujh, Srijita Dhar, Joshua A. Sommers, Arindam Datta, Gabriel M.C. Longo, Laura J. Grange, John J. Reynolds, Sophie L. Cooke, Gavin S. McNee, Robert Hollingworth, Beth L. Woodward, Anil N. Ganesh, Stephen J. Smerdon, Claudia M. Nicolae, Karina Durlacher-Betzer, Vered Molho-Pessach, Abdulsalam Abu-Libdeh, Vardiella Meiner, George-Lucian Moldovan, Vassilis Roukos, Tamar Harel, Robert M. Brosh Jr., Grant S. Stewart
Piezo1 forms mechanically-activated non-selective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial apoptosis, with no effect on thrombospondin-1 (TSP1), a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without effect on Tsp1. In the endothelial cells, Piezo1 was required for normal expression of endothelial nitric oxide synthase (eNOS). The data suggest an endothelial-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.
Fiona Bartoli, Marjolaine Debant, Eulashini Chuntharpursat-Bon, Elizabeth L. Evans, Katie E. Musialowski, Gregory Parsonage, Lara C. Morley, T. Simon Futers, Piruthivi Sukumar, T. Scott Bowen, Mark T. Kearney, Laeticia Lichtenstein, Lee D. Roberts, David J. Beech
Women have higher prevalence of asthma compared to men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed the androgen, dehydroepiandrosterone (DHEA), reduced asthma symptoms in patients, and mouse studies showed androgen receptor (AR) signaling decreased allergic airway inflammation. Yet, the role of AR signaling on lung Tregs remains unclear. Using AR deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext, allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting Gata2 expression, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.
Vivek D. Gandhi, Jacqueline-Yvonne Cephus, Allison E. Norlander, Nowrin U. Chowdhury, Jian Zhang, Zachary J. Ceneviva, Elie Tannous, Vasiliy V. Polosukhin, Nathan D. Putz, Nancy Wickersham, Amrit Singh, Lorraine B. Ware, Julie A Bastarache, Ciara M. Shaver, Hong Wei Chu, Ray S. Peebles Jr, Dawn C. Newcomb
Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no/low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that low ATP11B-expressing and high PTDSS2-expressing (ATP11Blow/PTDSS2high) cells were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11Blow/PTDSS2high phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressive cells (MDSCs) and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11Blow/PTDSSi2hgh cancer cells can be effectively overcome by changing the expression phenotype to ATP11Bhigh/PTDSS2low through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11Blow/PTDSS2high axis provided a new selective therapeutic strategy to prevent metastasis in breast cancer patients.
Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu
The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to, and growth of, solid tumors. Here we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages increased AML growth in-vivo. We showed that LAP is the predominate method of BM macrophage phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to accumulation of apoptotic cells (AC) and apoptotic bodies (AB) resulting in accelerated leukemia growth. Mechanistically, LAP of AMLderived-AB by BM macrophages, resulted in STING pathway activation. We identified that AML derived mitochondrial damage associated molecular patterns were processed by BM macrophages via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML derived-AB showed that it is this mtDNA which was responsible for the induction of STING signalling in BM macrophages. Phenotypically we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
Jamie A. Moore, Jayna J. Mistry, Charlotte Hellmich, Rebecca H. Horton, Edyta E. Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth
Obstructive arterial diseases including supravalvular aortic stenosis (SVAS), atherosclerosis and restenosis share two important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic or deletion mutations in the elastin gene ELN, and SVAS patients and elastin mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking as underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models as well as aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the Notch pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln(-/-) mutants. Eln(-/-) mice expressed higher levels of Notch ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln(-/-) mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.
Jui M. Dave, Raja Chakraborty, Aglaia Ntokou, Junichi Saito, Fatima Z. Saddouk, Zhonghui Feng, Ashish Misra, George Tellides, Robert K. Riemer, Zsolt Urban, Caroline Kinnear, James Ellis, Seema Mital, Robert Mecham, Kathleen A. Martin, Daniel M. Greif
Mutations in TAB2 (transforming growth factor β activated kinase 1 binding protein 2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing RIPK1 (receptor-interacting protein kinase 1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling following pathological stress. In cardiomyocytes, deletion of TAB2, but not its close homologue TAB3, promoted TNFα-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knock-in effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrate that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.
Haifeng Yin, Xiaoyun Guo, Yi Chen, Yachang Zeng, Xiaoliang Mo, Siqi Hong, Hui He, Jing Li, Rachel Steinmetz, Qinghang Liu
Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 Spike protein engaged the CD42b receptor to activate platelet via two distinct signaling pathways, and promoted platelet-monocyte communication through the engagement of P-selectin/PGSL-1 and CD40L/CD40, which led to pro-inflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation and a cytokine storm are correlated in severely affected COVID-19 patients, and suggest a potential target for therapeutic intervention.
Tianyang Li, Yang Yang, Yongqi Li, Zhengmin Wang, Faxiang Ma, Runqi Luo, Xiaoming Xu, Guo Zhou, Jianhua Wang, Junqi Niu, Guoyue Lv, Ian N Crispe, Zhengkun Tu
Exposure to addictive substances impairs flexible decision-making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 d) reduction of excitatory thalamic inputs onto CINs and reduced pause response of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.
Tengfei Ma, Zhenbo Huang, Xueyi Xie, Yifeng Cheng, Xiaowen Zhuang, Matthew J. Childs, Himanshu Gangal, Xuehua Wang, Laura N. Smith, Rachel J. Smith, Yubin Zhou, Jun Wang
Through their ability to regulate gene expression in most organs, glucocorticoid hormones influence numerous physiological processes and therefore are key regulators of organismal homeostasis. In bone, glucocorticoid hormones inhibit the expression of the hormone Osteocalcin for poorly understood reasons. Here we show that in a classical endocrine feedback loop, osteocalcin in return enhances the biosynthesis of glucocorticoid but also mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivating osteocalcin signalling in adrenal glands significantly impairs adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin is necessary for normal Sf1 expression in foetal adrenal cells and adrenal cell steroidogenic differentiation, it therefore determines the number of steroidogenic cells present in adrenal glands of adult animals. Embryonic not postnatal osteocalcin also governs adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium and the rise of circulating corticosterone during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurs even in the absence of a functional of hypothalamus-pituitary-adrenal axis; this explains why osteocalcin administration during pregnancy promotes adrenal growth and steroidogenesis and improves survival of adrenocorticotropic hormone signalling-deficient animals. This study reveals that a bone-derived, embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.
Vijay K. Yadav, Julian M. Berger, Parminder Singh, Perumal Nagarajan, Gerard Karsenty
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