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| Open AccessDrosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions
Vesicle transport ensures cargo delivery to cellular targets. Here, Soltani et al. show that Drosophila Evi5, a multiple sclerosis risk gene in humans, controls vesicular transport of iron-bound transferrins and physically interacts with ferritin.
- Sattar Soltani
- , Samuel M. Webb
- & Kirst King-Jones
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Article
| Open AccessA common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma
Type 2 inflammation drives the formation of pathologic mucus in patients with asthma. Here, authors reveal a role for intelectin-1 in IL-13-induced mucus properties, and that an ITLN1 eQTL is associated with protection from the formation of mucus plugs in T2-high asthma.
- Jamie L. Everman
- , Satria P. Sajuthi
- & Max A. Seibold
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Article
| Open AccessPersistent TFIIH binding to non-excised DNA damage causes cell and developmental failure
Hereditary nucleotide excision repair deficiencies cause different cancerous and progeroid disorders of which the exact etiology is not understood. This study finds that prolonged binding of DNA repair factor TFIIH to DNA damage contributes to a more severe phenotype caused by DNA repair deficiency.
- Alba Muniesa-Vargas
- , Carlota Davó-Martínez
- & Hannes Lans
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Article
| Open AccessTANGO1 inhibitors reduce collagen secretion and limit tissue scarring
Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring. Here the authors describe membrane permeable peptides that target the interface of TANGO1 and cTAGE5, inhibit secretion of ECM components and could be of therapeutic benefit during wound healing and fibrotic processes.
- Ishier Raote
- , Ann-Helen Rosendahl
- & Vivek Malhotra
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Article
| Open AccessNerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints
Osteoarthritis is a painful and debilitating condition. Here, the authors show that NGFR, a receptor for NGF, restricts NF-κB activation and its deficiency in skeletal cells impairs the remodeling and repair of osteoarthritic joints.
- Lan Zhao
- , Yumei Lai
- & Jian Huang
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Article
| Open AccessDeficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion
The mechanisms of bifurgation, a key step in thyroid development, are largely unknown. Here, Fang et al. find that HGF/Met is indispensable for the bifurgation of the thyroid primordium during zebrafish thyroid development.
- Ya Fang
- , Jia-Ping Wan
- & Huai-Dong Song
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Article
| Open AccessPRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects
PRPF8 is a hotspot for mutations causing retinitis pigmentosa-type 13. Here the authors generated PRPF8 patient-specific retinal cells, demonstrating an important role for this splicing factor in spliceosome kinetics and 5’ splice site selection.
- Robert Atkinson
- , Maria Georgiou
- & Majlinda Lako
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Article
| Open Accessp53 promotes revival stem cells in the regenerating intestine after severe radiation injury
The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.
- Clara Morral
- , Arshad Ayyaz
- & David G. Kirsch
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Article
| Open AccessTranslation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations
An emerging therapeutic strategy is to suppress nonsense mutations with engineered suppressor tRNAs. Here, the authors show that the mRNA translation velocity is a key parameter determining the efficacy of suppressor tRNAs.
- Nikhil Bharti
- , Leonardo Santos
- & Zoya Ignatova
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Article
| Open AccessStatins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1
Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.
- Bin Li
- , Wen-Wu Bai
- & Shuang-Xi Wang
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Article
| Open AccessMesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
- Cristiana Spinelli
- , Lata Adnani
- & Janusz Rak
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Article
| Open AccessEph-ephrin signaling couples endothelial cell sorting and arterial specification
Arteries are vital blood vessels for our body and their growth and patterning are critical for proper blood flow. Here they use a retina model to show that a balance of EphB4 receptor and ephrin-B2 ligand integrate a well-wired molecular network to control arteriovenous patterning and vascular growth.
- Jonas Stewen
- , Kai Kruse
- & Mara E. Pitulescu
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Article
| Open AccessA negative feedback loop between TET2 and leptin in adipocyte regulates body weight
The epigenetic regulation in adipocytes during obesity remains poorly understood. Here, the authors demonstrate a negative feedback loop between TET2, a DNA demethylation enzyme, and leptin, an adipokine, in adipocytes, unveiling a compensatory mechanism by which the body counteracts the metabolic dysfunction induced by obesity.
- Qin Zeng
- , Jianfeng Song
- & Tuo Deng
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Article
| Open AccessPCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor
Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to an increase of LDL cholesterol in blood. Here the authors show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor.
- Dasom Shin
- , Soungchan Kim
- & Hyo-Soo Kim
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Article
| Open AccessLong noncoding RNA Malat1 protects against osteoporosis and bone metastasis
MALAT1 is a long non-coding RNA that is known to suppress breast cancer lung metastasis. Here the authors show that MALAT1 is downregulated during osteoclastogenesis and its loss derepresses Tead3, promoting Nfatc1-mediated osteoclast differentiation and enhancing bone metastasis.
- Yang Zhao
- , Jingyuan Ning
- & Li Ma
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Article
| Open AccessNME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia
NME3 is a member of NDPK family. Here, Chen et. al., discover that histidine phosphorylatable NME3 is required for hypoxia-induced mitophagy via PA-dependent interaction with Drp1, which is protected from MUL1-mediated ubiquitination for mitophagy.
- Chih-Wei Chen
- , Chi Su
- & Zee-Fen Chang
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Article
| Open AccessBiallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Most individuals with primary familial brain calcification (PFBC) remain genetically unsolved. Here the authors show that NAA60 biallelic variants cause PFBC, likely via reduced N-terminal acetylation and SLC20A2 levels with impaired phosphate uptake.
- Viorica Chelban
- , Henriette Aksnes
- & Henry Houlden
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Article
| Open AccessTERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells
Here the authors show that the telomere repeat-containing RNA (TERRA) undergoes phase separation with the lysine-specific demethylase 1A (LSD1) to promote R-loop formation for homology-directed telomere DNA synthesis in the alternative lengthening of telomere (ALT) pathway.
- Meng Xu
- , Dulmi Senanayaka
- & Huaiying Zhang
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Article
| Open AccessDJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
- Aizhan Akhmadi
- , Adilkhan Yeskendir
- & Darkhan Utepbergenov
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Article
| Open Accessfhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
Extraocular muscles remain unaffected in muscular dystrophies. Here, the authors show that the gene fhl2b has a protective role in extraocular muscle and that its protective function can be applied to rescue other muscles in a zebrafish model of muscular dystrophy.
- Nils Dennhag
- , Abraha Kahsay
- & Fatima Pedrosa Domellöf
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Article
| Open AccessMYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Several molecular mechanisms, including retinoblastoma protein RB1 deficiency, explain CDK4/6 inhibitors resistance in cancer. Here, the authors show that MYC amplification induces CDK4/6 inhibitors resistance through transcriptional regulation of KLHL42, leading to RB1 degradation and targeting MYC overcomes CDK4/6 resistance in preclinical cancer models.
- Jian Ma
- , Lei Li
- & Lei Li
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Article
| Open AccessNINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Fevers are known to be both beneficial and detrimental in disease, but the fundamental innate immune mechanisms driving pathology in this context remain unclear. Here, the authors show that a combination of LPS and heat stress induces inflammatory cell death, PANoptosis, that is dependent on the executioner molecule Ninjurin 1 (Ninj1) to release inflammatory molecules and drive pathogenesis.
- Joo-Hui Han
- , Rajendra Karki
- & Thirumala-Devi Kanneganti
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Article
| Open AccessTargeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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Article
| Open AccessElevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions
Extracellular vesicles are reported to regulate tumorigenesis. Here, the authors show that under obesity conditions, increased extracellular matrix protein 1 protein levels in circulating small extracellular vesicles induce breast cancer growth and metastasis.
- Keyang Xu
- , Ai Fu
- & Hiu Yee Kwan
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Article
| Open AccessStalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis
Ribosome associated quality control (RQC) is a new area of biological investigation with emerging connection to a broad range of diseases. Here authors show that mitochondrial stress can upregulate a new RQC pathway important for tissue homeostasis.
- Ji Geng
- , Shuangxi Li
- & Bingwei Lu
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Article
| Open AccessGenome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Mechanisms regulating collagen clearance may be useful for treating fibrosis. Here, the authors conducted functional genome-wide screens and found that collagen biosynthesis directly regulates collagen clearance via a noncanonical function of SEL1L.
- Michael J. Podolsky
- , Benjamin Kheyfets
- & Kamran Atabai
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Article
| Open AccessA single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Article
| Open AccessSingle-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis
Anti-integrin therapy inhibits lymphocyte trafficking in ulcerative colitis. Here Mennillo et al. use single-cell and spatial -omics to show modulation of mononuclear phagocytes and other networks, identifying gene sets related to treatment response.
- Elvira Mennillo
- , Yang Joon Kim
- & Michael G. Kattah
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Article
| Open AccessAggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Mutations in rhodopsin can cause the receptor to aggregate, however, it is unclear whether this molecular defect underlies the retinal degeneration in autosomal dominant retinitis pigmentosa. Here, the authors show the potential for rhodopsin aggregates to play a role in retinal degeneration.
- Sreelakshmi Vasudevan
- , Subhadip Senapati
- & Paul S.–H. Park
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Article
| Open AccessPAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma
MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.
- Abdallah Gaballa
- , Anneli Gebhardt-Wolf
- & Martin Eilers
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Article
| Open AccessChp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis
Here the authors discover a dedicated ribosome-associated chaperone, Chp1, that assists in the challenging biogenesis of eukaryotic translation elongation factor 1A (eEF1A) by cotranslationally stabilizing the growing GTPase domain of eEF1A.
- Melania Minoia
- , Jany Quintana-Cordero
- & Claes Andréasson
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Article
| Open AccessNeurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile myogenic progenitors
The establishment of the postnatal skeletal muscle stem cell pool is not well understood. Here the authors show a requirement for Nf1 to coordinate muscle fiber growth and stem cell quiescence induction, and to prevent detrimental metabolic reprogramming with life-long consequences.
- Xiaoyan Wei
- , Angelos Rigopoulos
- & Sigmar Stricker
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Article
| Open AccessAdipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape
Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.
- Isabel Reinisch
- , Helene Michenthaler
- & Andreas Prokesch
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Article
| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li
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Article
| Open AccessPalmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability. Here, the authors show that elevated palmitic acid levels are linked to increased atherosclerotic plaque vulnerability.
- Xiqiang Wang
- , Ling Zhu
- & Zhongwei Liu
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Article
| Open AccessMechanistic characterization of a Drosophila model of paraneoplastic nephrotic syndrome
The fruit fly Drosophila melanogaster has emerged as a model to characterize the mechanisms of tumor-induced host organ dysfunction. Here, Xu, Liu et al. describe a mechanism of tumor-induced kidney dysfunction through hyper-activation of the PvR/JNK/Jra pathway in the Principal cells of the fly kidney/Malpighian tubules.
- Jun Xu
- , Ying Liu
- & Norbert Perrimon
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Article
| Open AccessAndrogen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation
Mechanisms underlying sex associated differences in the role of androgen receptor (AR) in melanoma are unclear. Here the authors show that androgen-activated AR transcriptionally upregulates fucosyltransferase 4, which fucosylates L1CAM and promotes melanoma invasiveness by disrupting adherens junctions.
- Qian Liu
- , Emma Adhikari
- & Eric K. Lau
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Article
| Open AccessCDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver
Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.
- Alexander J. Hu
- , Wei Li
- & Miaofen G. Hu
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Article
| Open AccessExpression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells
The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been associated with primary biliary cholangitis. Here, the authors demonstrate that CD8+ T cells invade BEC using a mechanism that is dependent on cytoskeletal rearrangements and E-cadherin:β-catenin interactions.
- Scott P. Davies
- , Vincenzo Ronca
- & Ye H. Oo
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Article
| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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Article
| Open AccessUpregulated pexophagy limits the capacity of selective autophagy
An accumulation of one substrate of selective autophagy can lead to autophagic degradation deficiencies. Here, the authors show that a pathogenic increase in a single autophagy pathway restricts another by consuming the cell’s autophagy capacity.
- Kyla Germain
- , Raphaella W. L. So
- & Peter K. Kim
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Article
| Open AccessVariants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
A vesicle trafficking Rab11 effector switch is important for ciliogenesis. Here, the authors report a ciliopathy-related disorder caused by variants in WDR44, a Rab11 effector. WDR44 variants show higher affinity for Rab11 and can impair ciliogenesis.
- Andrea Accogli
- , Saurabh Shakya
- & Christopher J. Westlake
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Article
| Open AccessTargeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open AccessMulti-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.
- Julia Schöpf
- , Sebastian Uhrig
- & Claudia Scholl
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Article
| Open AccessSerglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessBACH1 controls hepatic insulin signaling and glucose homeostasis in mice
Hepatic insulin resistance plays a central role in metabolic syndrome. Here, the authors show that transcription factor BACH1 acts as a negative regulator of insulin signaling and that hepatic BACH1 deficiency ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or diabetic mice
- Jiayu Jin
- , Yunquan He
- & Dan Meng
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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessNEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62
Selective autophagy helps to degrade aggregated proteins accumulating in neurodegenerative diseases. Here, the authors show that NEMO, a ubiquitin binding protein previously linked to innate immune signaling, is recruited to misfolded proteins and promotes their autophagic clearance by forming condensates with the autophagy receptor p62.
- Nikolas Furthmann
- , Verian Bader
- & Konstanze F. Winklhofer