ABSTRACT
Perovskite solar cells (PSCs) are among the most promising photovoltaic technologies owing to their exceptional optoelectronic properties1,2. However, the lower efficiency, poor stability and reproducibility issues of large-area PSCs compared with laboratory-scale PSCs are notable drawbacks that hinder their commercialization3. Here we report a synergistic dopant-additive combination strategy using methylammonium chloride (MACl) as the dopant and a Lewis-basic ionic-liquid additive, 1,3-bis(cyanomethyl)imidazolium chloride ([Bcmim]Cl). This strategy effectively inhibits the degradation of the perovskite precursor solution (PPS), suppresses the aggregation of MACl and results in phase-homogeneous and stable perovskite films with high crystallinity and fewer defects. This approach enabled the fabrication of perovskite solar modules (PSMs) that achieved a certified efficiency of 23.30% and ultimately stabilized at 22.97% over a 27.22-cm2 aperture area, marking the highest certified PSM performance. Furthermore, the PSMs showed long-term operational stability, maintaining 94.66% of the initial efficiency after 1,000 h under continuous one-sun illumination at room temperature. The interaction between [Bcmim]Cl and MACl was extensively studied to unravel the mechanism leading to an enhancement of device properties. Our approach holds substantial promise for bridging the benchtop-to-rooftop gap and advancing the production and commercialization of large-area perovskite photovoltaics.
ABSTRACT
Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200-ATG13-ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200-ATG13-ULK1 complex. TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels. However, during starvation-induced autophagy, TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1. This cooperative mechanism serves to restrain the amplitude and duration of autophagy. Further evidence from mouse models shows that basal autophagy levels are increased in Trim27 knockout mice and that Trim27 differentially regulates tumorigenesis and metastasis. Our study identifies a key role of STK38L-TRIM27-ULK1 signaling axis in negatively controlling autophagy with relevance established in human breast cancer.
Subject(s)
Autophagy , Protein Serine-Threonine Kinases , Animals , Autophagy-Related Protein-1 Homolog/genetics , Carcinogenesis/genetics , DNA-Binding Proteins , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mice , Nuclear Proteins , Protein Serine-Threonine Kinases/genetics , Serine , Transcription Factors , Ubiquitin-Protein LigasesABSTRACT
DNA and histone modifications have notable effects on gene expression1. Being the most prevalent internal modification in mRNA, the N6-methyladenosine (m6A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2-4 and has crucial roles in various normal and pathological processes5-12. However, it is unclear how m6A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. We show that m6A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m6A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m6A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.
Subject(s)
Adenosine/analogs & derivatives , Histones/chemistry , Histones/metabolism , Lysine/metabolism , RNA, Messenger/chemistry , RNA, Messenger/metabolism , Transcription, Genetic , Adenosine/metabolism , Animals , Cell Differentiation , Cell Line , Embryonic Stem Cells/metabolism , Humans , Lysine/chemistry , Methylation , Methyltransferases/deficiency , Methyltransferases/genetics , Methyltransferases/metabolism , Mice , RNA Polymerase II/metabolism , Transcription Elongation, Genetic , Transcriptome/geneticsABSTRACT
SignificanceMolecules interacting with metallic nanostructures can show tunable exciton-plasmon coupling, ranging from weak to strong. One factor that influences the interactions is the spatial organization of the molecules relative to the localized plasmon-enhanced electromagnetic fields. In this work, we show that the arrangement of aromatic dye molecules can be tuned within plasmonic hotspots by interfacial engineering of nanoparticle surfaces. By controlling the local chemical and physical interactions, we could modulate lasing thresholds. Surface-functionalized plasmonic metasurfaces open prospects for programmable light-matter interactions at the nanoscale.
ABSTRACT
Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.
Subject(s)
Autophagy , Intestines , Receptor, Platelet-Derived Growth Factor alpha , Stem Cells , Animals , Autophagy/genetics , Autophagy-Related Protein 5 , Autophagy-Related Protein 7 , Autophagy-Related Proteins , Cell Survival , Mice , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Stem Cells/metabolismABSTRACT
This paper reports how a hybrid system composed of transparent dielectric lattices over a metal mirror can produce high-quality lattice resonances for unidirectional lasing. The enhanced electromagnetic fields are concentrated in the cladding of the periodic dielectric structures and away from the metal. Based on a mirror-image model, we reveal that such high-quality lattice resonances are governed by bound states in the continuum resulting from destructive interference. Using hexagonal arrays of titanium dioxide nanoparticles on a silica-coated silver mirror, we observed lattice resonances with quality factors of up to 2750 in the visible regime. With the lattice resonances as optical feedback and dye solution as the gain medium, we demonstrated unidirectional lasing under optical pumping, where the array size was down to 100 µm × 100 µm. Our scheme can be extended to other spectral regimes to simultaneously achieve strongly enhanced surface fields and high quality factors.
ABSTRACT
Electrohydrodynamic printing holds both ultrahigh-resolution fabrication capability and unmatched ink-viscosity compatibility yet fails on highly insulating thick/irregular substrates. Herein, we proposed a single-potential driven electrohydrodynamic printing process with submicrometer resolution on arbitrary nonconductive targets, regardless of their geometric shape or sizes, via precoating with an ultrathin dielectric nanoparticle layer. Benefiting from the favorable Maxwell-Wagner polarization, the reversely polarized spot brought about a significant drop (â¼57% for ceramics) in the operation voltage as its induced electric field and a negligible residual charge accumulation. Thus, ordered micro/nanostructures with line widths down to 300 nm were directly written at a stage speed as low as 5 mm/s, and silver features with width of â¼2 µm or interval of â¼4 µm were achieved on insulating substrates separately. Flexible sensors and curved heaters were then high-precision printed and demonstrated successfully, presenting this technique with huge potential for fabricating flexible/conformal electronics on arbitrary 3D structures.
ABSTRACT
Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.
Subject(s)
Breast Neoplasms , Histone Demethylases , Molecular Targeted Therapy , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Histone Demethylases/antagonists & inhibitors , Histone Demethylases/metabolism , Histone Demethylases/genetics , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Jumonji Domain-Containing Histone Demethylases/metabolism , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Jumonji Domain-Containing Histone Demethylases/genetics , Biomarkers, TumorABSTRACT
Heat shock cognate protein 70 (Hsc70/HSPA8) belongs to the Hsp70 family of molecular chaperones. The fundamental functions of Hsp70 family molecular chaperones depend on ATP-dependent allosteric regulation of binding and release of hydrophobic polypeptide substrates. Hsc70 is also involved in various other cellular functions including selective pathways of protein degradation: chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), in which Hsc70 recruits substrate proteins containing a KFERQ-like pentapeptide motif from the cytosol to lysosomes and late endosomes, respectively. However, whether the interaction between Hsc70 and the pentapeptide motif is direct or mediated by other molecules has remained unknown. In the present study, we introduced a photo-crosslinker near the KFERQ motif in a CMA/eMI model substrate and successfully detected its crosslinking with Hsc70, revealing the direct interaction between Hsc70 and the KFERQ motif for the first time. In addition, we demonstrated that the loss of the Hsc70 ATPase activity by the D10 N mutation appreciably reduced the crosslinking efficiency. Our present results suggested that the ATP allostery of Hsc70 is involved in the direct interaction of Hsc70 with the KFERQ-like pentapeptide.
ABSTRACT
IMPORTANCE: Although Micropterus salmoides rhabdovirus (MSRV) causes serious fish epidemics worldwide, the detailed mechanism of MSRV entry into host cells remains unknown. Here, we comprehensively investigated the mechanism of MSRV entry into epithelioma papulosum cyprinid (EPC) cells. This study demonstrated that MSRV enters EPC cells via a low pH, dynamin-dependent, microtubule-dependent, and clathrin-mediated endocytosis. Subsequently, MSRV transports from early endosomes to late endosomes and further into lysosomes in a microtubule-dependent manner. The characterization of MSRV entry will further advance the understanding of rhabdovirus cellular entry pathways and provide novel targets for antiviral drug against MSRV infection.
Subject(s)
Bass , Rhabdoviridae , Animals , Rhabdoviridae/metabolism , Bass/metabolism , rab5 GTP-Binding Proteins/metabolism , Endocytosis , Dynamins/metabolism , Microtubules/metabolism , Clathrin/metabolism , Hydrogen-Ion Concentration , Virus InternalizationABSTRACT
The Hedgehog (Hh) signaling pathway is involved in T cell differentiation and development and plays a major regulatory part in different stages of T cell development. A previous study by us suggested that prenatal exposure to staphylococcal enterotoxin B (SEB) changed the percentages of T cell subpopulation in the offspring thymus. However, it is unclear whether prenatal SEB exposure impacts the Hh signaling pathway in thymic T cells. In the present study, pregnant rats at gestational day 16 were intravenously injected once with 15 µg SEB, and the thymi of both neonatal and adult offspring rats were aseptically acquired to scrutinize the effects of SEB on the Hh signaling pathway. It firstly found that prenatal SEB exposure clearly caused the increased expression of Shh and Dhh ligands of the Hh signaling pathway in thymus tissue of both neonatal and adult offspring rats, but significantly decreased the expression levels of membrane receptors of Ptch1 and Smo, transcription factor Gli1, as well as target genes of CyclinD1, C-myc, and N-myc in Hh signaling pathway of thymic T cells. These data suggest that prenatal SEB exposure inhibits the Hh signaling pathway in thymic T lymphocytes of the neonatal offspring, and this effect can be maintained in adult offspring via the imprinting effect.
Subject(s)
Enterotoxins , Hedgehog Proteins , Signal Transduction , T-Lymphocytes , Thymus Gland , Animals , Hedgehog Proteins/metabolism , Hedgehog Proteins/genetics , Female , Pregnancy , Rats , Thymus Gland/metabolism , Thymus Gland/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Zinc Finger Protein GLI1/metabolism , Zinc Finger Protein GLI1/genetics , Patched-1 Receptor/metabolism , Patched-1 Receptor/genetics , Smoothened Receptor/metabolism , Smoothened Receptor/genetics , Prenatal Exposure Delayed Effects/immunology , Cell Differentiation/drug effects , Rats, Sprague-Dawley , MaleABSTRACT
BACKGROUND: The effects of the decline in health care use at the start of the COVID-19 pandemic on the health of children are unclear. We sought to estimate changes in rates of severe and potentially preventable health outcomes among children during the pandemic. METHODS: We conducted a repeated cross-sectional study of children aged 0-17 years using linked population health administrative and disease registry data from January 2017 through August 2022 in Ontario, Canada. We compared observed rates of emergency department visits and hospital admissions during the pandemic to predicted rates based on the 3 years preceding the pandemic. We evaluated outcomes among children and neonates overall, among children with chronic health conditions and among children with specific diseases sensitive to delays in care. RESULTS: All acute care use for children decreased immediately at the onset of the pandemic, reaching its lowest rate in April 2020 for emergency department visits (adjusted relative rate [RR] 0.28, 95% confidence interval [CI] 0.28-0.29) and hospital admissions (adjusted RR 0.43, 95% CI 0.42-0.44). These decreases were sustained until September 2021 and May 2022, respectively. During the pandemic overall, rates of all-cause mortality, admissions for ambulatory care-sensitive conditions, newborn readmissions or emergency department visits or hospital admissions among children with chronic health conditions did not exceed predicted rates. However, after declining significantly between March and May 2020, new presentations of diabetes mellitus increased significantly during most of 2021 (peak adjusted RR 1.49, 95% CI 1.28-1.74 in July 2021) and much of 2022. Among these children, presentations for diabetic ketoacidosis were significantly higher than expected during the pandemic overall (adjusted RR 1.14, 95% CI 1.00-1.30). We observed similar time trends for new presentations of cancer, but we observed no excess presentations of severe cancer overall (adjusted RR 0.91, 95% CI 0.62-1.34). INTERPRETATION: In the first 30 months of the pandemic, disruptions to care were associated with important delays in new diagnoses of diabetes but not with other acute presentations of select preventable conditions or with mortality. Mitigation strategies in future pandemics or other health system disruptions should include education campaigns around important symptoms in children that require medical attention.
Subject(s)
COVID-19 , Neoplasms , Child , Infant, Newborn , Humans , COVID-19/epidemiology , Pandemics , Ontario/epidemiology , Cross-Sectional Studies , Emergency Service, Hospital , Delivery of Health CareABSTRACT
This Review focuses on the integration of plasmonic and dielectric metasurfaces with emissive or stimuli-responsive materials for manipulating light-matter interactions at the nanoscale. Metasurfaces, engineered planar structures with rationally designed building blocks, can change the local phase and intensity of electromagnetic waves at the subwavelength unit level and offers more degrees of freedom to control the flow of light. A combination of metasurfaces and nanoscale emitters facilitates access to weak and strong coupling regimes for enhanced photoluminescence, nanoscale lasing, controlled quantum emission, and formation of exciton-polaritons. In addition to emissive materials, functional materials that respond to external stimuli can be combined with metasurfaces to engineer tunable nanophotonic devices. Emerging metasurface designs including surface-functionalized, chemically tunable, and multilayer hybrid metasurfaces open prospects for diverse applications, including photocatalysis, sensing, displays, and quantum information.
ABSTRACT
The exploration of deep space significantly increases the probability of spacecraft failures due to surface electrostatic discharge, which imposes higher vacuum insulation protection requirements on polyimide, the external insulation material of spacecrafts. To address this challenge, this study proposes using silane coupling agent KH550 for organic grafting treatment of Cr2O3 nanoparticles, which are then used to dope and modify polyimide to enhance the vacuum surface insulation of polyimide films. The KH550 grafting improves the interface strength between the fillers and the matrix, allowing the fillers to be uniformly dispersed in the matrix. Compared to pure polyimide films, the prepared PI-Cr2O3@KH550 composite films exhibit significantly enhanced vacuum surface flashover voltage, improved surface/volume resistivity, and dielectric properties. The results demonstrate that polyimide composite films with 0.8% by mass of Cr2O3@KH550 show the most notable performance improvement, with the DC flashover voltage and impulse flashover voltage in vacuum increasing by 20.7% and 27.8%, respectively. The doping of chromium oxide nanoparticles introduces more deep traps into the polyimide films and reduce the surface resistivity. The higher deep trap density inhibits charge migration, thereby alleviating secondary electron emission and surface electric field distortion. Simultaneously, the lower surface resistivity facilitates dissipating surface charges and improves the surface insulation. These findings are of significant reference value for promoting the enhancement of aerospace insulation performance.
ABSTRACT
Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.
Subject(s)
Neoplasms , Ubiquitin Thiolesterase , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/metabolism , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitin Thiolesterase/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Animals , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Molecular StructureABSTRACT
RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.
Subject(s)
Drug Discovery , Epigenesis, Genetic , Homeostasis , RNA , RNA, MessengerABSTRACT
Marine macroalgae are increasingly recognized for their significant biological and economic potential. The key to unlocking this potential lies in the efficient degradation of all carbohydrates from the macroalgae biomass. However, a variety of polysaccharides (alginate, cellulose, fucoidan, and laminarin), are difficult to degrade simultaneously in a short time. In this study, the brown alga Saccharina japonica was found to be rapidly and thoroughly degraded by the marine bacterium Agarivorans albus B2Z047. This strain harbors a broad spectrum of carbohydrate-active enzymes capable of degrading various polysaccharides, making it uniquely equipped to efficiently break down both fresh and dried kelp, achieving a hydrolysis rate of up to 52%. A transcriptomic analysis elucidated the presence of pivotal enzyme genes implicated in the degradation pathways of alginate, cellulose, fucoidan, and laminarin. This discovery highlights the bacterium's capability for the efficient and comprehensive conversion of kelp biomass, indicating its significant potential in biotechnological applications for macroalgae resource utilization.
Subject(s)
Phaeophyceae , Polysaccharides , Seaweed , Seaweed/metabolism , Phaeophyceae/metabolism , Polysaccharides/metabolism , Hydrolysis , Biomass , Glucans/metabolism , Flavobacteriaceae/metabolism , Kelp/metabolismABSTRACT
In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.
Subject(s)
Ascorbic Acid , Nimodipine , Rats , Animals , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme SystemABSTRACT
Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582-585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo.
Subject(s)
Autophagy/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Animals , Apoptosis/physiology , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Autophagy-Related Proteins , Cell Proliferation/genetics , Disease Models, Animal , Embryonic Development/genetics , Female , Gene Knock-In Techniques , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Nude , Mutation , Survival Analysis , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.