AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy ...homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.
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•MAGE-A3/6 are normally testis restricted and aberrantly expressed in many cancers•MAGE-A3/6 are driver oncogenes competent to transform cells•MAGE-A3/6-TRIM28 ubiquitinates and degrades the AMPK tumor suppressor•MAGE-A3/6-TRIM28 suppresses autophagy and potentiates mTOR signaling
A cancer-specific E3 ubiquitin ligase ubiquitinates and degrades AMPK, resulting in downregulation of autophagy and increased mTOR signaling. This regulatory axis demonstrates how altered cellular metabolism can act as an oncogenic driver in cancer.
Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines ...depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca
influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca
channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). This study demonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operated Ca
influx (nSOC) channel complex in hippocampal synapse and the resulting Ca
influx is critical for long-term maintenance of mushroom spines in hippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescues mushroom spine loss and synaptic plasticity impairment in AD mice models. The TRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating ...protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.
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•USP7 is part of the MAGE-L2-TRIM27 ubiquitin ligase and enables endosomal recycling•USP7 protects TRIM27 from auto-ubiquitination and proteasomal degradation•USP7 buffers WASH ubiquitination levels to maintain proper endosomal actin levels•Mutation of USP7 causes a human neurodevelopmental syndrome, including autism
Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.
With this issue, we will close 2023 and it is my distinct pleasure to summarize the continued improvements of the Slovenian Veterinary Research journal we’ve made this year. To advance authors’, ...reviewers’, and readers’ experiences, we first updated the Open Journal System. We continuously revise and develop our instructions for authors, reviewers, and editors to streamline the pathway from submission to publication and make it easier for all. We have updated the graphical image of the journal, invited an artist to the Editorial team, and started featuring our manuscripts with illustrated artwork on the cover of the journal. With this, we want to emphasize the published work and novel discoveries, but also strengthen the interconnectedness of science and art. Furthermore, we emphasize manuscripts published in our journal or work pertinent to the discoveries on disease pathophysiology, therapy, prevention, and public health by short articles, and editorials...
Refleksija in pogled naprej – vloga veterinarskih znanstvenih revij v veterinarskih raziskavah in medicini
S to številko smo zaključili leto 2023 in v posebno veselje mi je opozoriti na novosti, ki smo jih opravili v tem letu. Da bi izboljšali izkušnje avtorjev, recenzentov in bralcev, smo posodobili sistem odprtega dostopa. Po potrebi prilagajamo navodila za avtorje, recenzente in urednike, vse z namenom izboljšanja postopkov do objave prispevkov.Letos smo spremenili tudi grafično podobo revije in v uredništvo povabili akademsko ilustratorko. Z njenimi ilustracijami, ki krasijo naslovnice posameznih števlk, predstavljavljamo nekatere objavljene prispevke, s čimer opozarjamo na znanstveno aktualne teme in novejša odkritja, hkrati pa krepimo povezovanje z umetnostjo. S kratkimi uvodniki večkrat izpostavljamo posamezne objavjene članke, ki obravnavajo znanstveno tematiko iz področij javnega zdravja, patofiziologije, terapije in preventive bolezni...
The melanoma antigen (MAGE) proteins all contain a MAGE homology domain. MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to ∼40 genes in humans and ...mice. Whereas some MAGEs are ubiquitously expressed in tissues, others are expressed in only germ cells with aberrant reactivation in multiple cancers. Much of the initial research on MAGEs focused on exploiting their antigenicity and restricted expression pattern to target them with cancer immunotherapy. Beyond their potential clinical application and role in tumorigenesis, recent studies have shown that MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases besides cancer, including lung, renal, and neurodevelopmental disorders. At the molecular level, many MAGEs bind to E3 RING ubiquitin ligases and, thus, regulate their substrate specificity, ligase activity, and subcellular localization. On a broader scale, the MAGE genes likely expanded in eutherian mammals to protect the germline from environmental stress and aid in stress adaptation, and this stress tolerance may explain why many cancers aberrantly express MAGEs. Here, we present an updated, comprehensive review on the MAGE family that highlights general characteristics, emphasizes recent comparative studies in mice, and describes the diverse functions exerted by individual MAGEs.
This year’s Nobel Prize in Physiology or Medicine has been awarded to Katalin Karikó and Drew Weissman for discoveries that enabled the development of messenger RNA (mRNA) vaccines against COVID-19. ...mRNA is a transient molecule in the cell that conveys the instructions for synthesis of a protein from the nucleus, where instructions are stored as a genetic code in the DNA, to the cell’s protein making machinery (ribosomes) in the cytoplasm. It took several decades of research to uncover how mRNA could be used to deliver an antigen into cells and trigger the body’s own immune response.
NOBELOVA NAGRADA 2023 ZA FIZIOLOGIJO ALI MEDICINO: POT DO NASLEDNJEGA RODU CEPIV
Letošnja Nobelova nagrada za fiziologijo ali medicino je bila podeljena Katalin Karikó in Drewu Weissmanu za odkritja, ki so omogočila razvoj cepiv proti COVID-19 na osnovi sporočilne RNA (mRNA). mRNA je prehodna molekula v celici, ki posreduje navodila za sintezo proteinov iz jedra, kjer so navodila shranjena kot genetski kod v DNA, celičnemu sistemu za izdelovanje proteinov (ribosomov) v citoplazmi. Potrebnih je bilo več desetletij raziskav, da bi odkrili, kako uporabiti mRNA za prenos antigenov celicam in začetek telesu lastnega imunskega odziva.
Ključne besede: Nobelova nagrada; mRNA cepiva; genska terapija
Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. ...Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
We determine the mRNA expression patterns of the fibroblast growth factors, their receptors and associated proteins in 39 adult mouse tissues.
Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic ...expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption.
Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin ...resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver), through nonalcoholic steatohepatitis (NASH) to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD), and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.
The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in ...patients with Prader–Willi (PWS) and Schaaf–Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, MAGEL2. Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly MAGEL2, affects the molecular mechanisms of hormone secretion. These results suggest that MAGEL2 evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function.
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