Biology subjects

Gao, K.

Publications and source records attributed to Gao, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Programmable Surface Receptor-Mediated Cell Targeting with Designer Antibody-Routed Nanoparticles (DARTs)

Precise in vivo delivery remains a massive barrier to therapeutic genome editing. Recently, major strides have been made towards cell type-specific delivery, with potential to improve the safety profiles of future gene therapies. However, programming such targeted tropism is limited by the minimal repertoire of scFv sequences, nanobodies, and viral fusogens that enable cell-type specificity, and the slow, iterative design-build-test cycle required to identify and optimize them. Here, we overcome this bottleneck by developing the designer antibody-routed (DART) platform: a modular, plug-and-play tool that decouples delivery vehicle production from tropism engineering. By presenting generic, bioorthogonal antibody-binding interfaces on the surfaces of enveloped particles, the DART system enables conjugation of those particles with off-the-shelf antibodies that direct cell entry without requiring genetic or chemical manipulation. Designer antibody-routed virus-like particles (DARTs) leverage this facile conjugation method to interrogate and identify transduction-competent surface antigens across cell types. They enable combinatorial targeting and the discovery of antigens that synergistically enhance transduction. Finally, DARTs function in the fetal murine nervous system, empirically identifying CD56 as a previously uncharacterized surface antigen enabling editing in hard-to-transduce neural populations. Overall, the DART platform provides a universal tool for rapidly profiling unique, targetable antigens and leveraging them for precision editing applications.

bioengineering↗

bioRxiv2026

PPARγ brakes cytosolic DNA-induced macrophage inflammation by super-enhancer metabolic reprogramming

Cytoplasmic DNA sensing triggers intense innate immune responses that require tight regulation. PPAR{gamma} is a master metabolic regulator in macrophages, but its role in cytoplasmic DNA immunity remains unclear. Using poly(dA:dT) to mimic cytoplasmic DNA stimulation, we combined transcriptomics, epigenomics (PPAR{gamma}/H3K27ac ChIP-seq), and functional assays. Poly(dA:dT) induced a cytokine storm with MAPK activation and apoptosis/necrosis. PPAR{gamma} activation by rosiglitazone (RGZ) antagonized this response, reducing cell death and transcriptionally inhibiting MAPK genes (e.g., DUSP4/10). Mechanistically, PPAR{gamma} bound promoters/enhancers via PPRE motifs and distal intergenic regions, remodeling H3K27ac (reduced at inflammatory loci, increased at metabolic genes). RGZ induced de novo super-enhancers coupling PPAR metabolic programs (e.g., CPT2) with immune suppression by targeting TLR4, CEBPB, and PIM3. Thus, PPAR{gamma} acts as a brake in cytoplasmic DNA immunity, integrating metabolic reprogramming and inflammation suppression through a multi-level genomic/epigenetic program. This study highlights PPAR{gamma} as a key immune-metabolic integrator and therapeutic target for diseases driven by excessive cytoplasmic DNA sensing.

immunology↗

bioRxiv2025

Sensory receptor expansion and neural accommodation in butterfly color vision

The evolution of complex brains required existing neurons and neural circuits to accommodate new inputs. The genetic and developmental mechanisms that enable such integration are largely unknown. Butterflies evolved more complex retinal mosaics through the addition of a second R7 color photoreceptor per ommatidium (unit eye). In Drosophila, the unique R7 makes a stochastic choice to express one of two opsin genes. In butterflies, the two R7s make independent stochastic cell fate choices in each ommatidium, producing three ommatidial types instead of two. Here, we investigate the developmental basis of this change and how the butterfly brain accommodates expanded sensory receptor input. We first identified the changes in gene expression that cause a second R7 cell to be specified. We then modified Drosophila retinas to have butterfly-like transcription factor expression, causing recruitment of an additional R7. The two R7s make independent stochastic choices, like butterflies, leading to three stochastically distributed ommatidial types. In Drosophila, the two R7 subtypes connect to their target neurons, either yDm8 or pDm8. Dm8 neurons of both types are born in excess and Dm8s that do not find connections with their cognate y or pR7s undergo apoptosis. In the presence of extra R7s in butterfly-like fly retinas, additional Dm8s are retained, leading to two Dm8s per medulla column that make appropriate connections with the matching R7 subtypes, facilitating the expansion of color vision. We propose that the presence of cells that would otherwise die provide developmental flexibility that can allow brains to accommodate newly evolved inputs.

developmental biology↗

bioRxiv2025

FlexRibbon: Joint Sequence and Structure Pretraining for Protein Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein foundation models have advanced rapidly, with most approaches falling into two dominant paradigms. Sequence-based language models (e.g., ESM-2) capture sequence semantics at scale, and a number of recent works incorporate structural signals into sequence encoders. MSA-based predictors (e.g., AlphaFold 2/3) achieve accurate folding by exploiting evolutionary couplings, but their reliance on homologous sequences makes them less reliable in highly mutated or alignment-sparse regimes. We present FlexRibbon{ddagger}, a pretrained protein model that jointly learns from amino acid sequences and three-dimensional structures. Our pretraining strategy combines masked language modeling with diffusion-based denoising, enabling bidirectional sequence-structure learning without requiring MSAs. Trained on both experimentally resolved structures and AlphaFold 2 predictions, FlexRibbon captures global folds as well as flexible conformations critical for biological function. Evaluated across diverse tasks spanning interface design, intermolecular interaction prediction, and protein function prediction, FlexRibbon establishes new state-of-the-art performance on 12 different tasks, with particularly strong gains in mutation-rich settings where MSA-based methods often struggle.

molecular biology↗

bioRxiv2025

An Objective Detection Method for Tinnitus using Memristors

Approximately 10-20% of the world population experiences tinnitus, which is increased with age and comorbid with frustration, annoyance, anxiety, depression, cognitive dysfunction, insomnia and stress. The underlying mechanisms of tinnitus remain largely unknown and there are no quantifiable biomarkers, making this prevalent disorder a global burden. There are no FDA-approved therapeutics and the current assessment mainly relies on self-reports (e.g., questionnaires), which underscore the need for diagnostic tools for tinnitus. Memristors, nanoscale electronic components mimicking synaptic plasticity, can monitor and control neuronal activity, hold transformative potential for detecting and characterizing tinnitus objectively. Here, we harvested the blood from human and mice with tinnitus, and engineered memristors via magnetron sputtering and made the functional layer with serum. Its core mechanism lies in regulating the reversible formation and rupture of conductive filaments which is formed by utilizing abnormally elevated glutamate concentrations in serum assisted Ag+ ions. This serum-based memristor achieves unprecedented discrimination between tinnitus and non-tinnitus individuals. Furthermore, this platform provides mechanistic insights into tinnitus pathogenesis, with potential implications in other neurological disorders.

pathology↗

bioRxiv2025

Population genomics of the endangered scaly-foot snail defines conservation units amid deep-sea mining threats in Indian Ocean vents

Hydrothermal vents in the Indian Ocean face imminent deep-sea mining, yet lack baseline high-resolution connectivity data for their endemic fauna. We present the first population genomic study of the endangered scaly-foot snail (Chrysomallon squamiferum), an iconic species distributed across three vent biogeographic provinces. Analysing 125 individuals from eight vent fields using 14 million single-nucleotide polymorphisms, we identify five genetic groups that warrant recognition as evolutionarily significant units. Demographic modelling reveals critical contributions from extinct or unsampled phantom populations to the contemporary genetic structure. Together with physical ocean modelling, we show that the deep currents drive asymmetric south-to-north gene flows, while transform faults act as dispersal barriers. We propose Longqi-Duanqiao fields on the Southwest Indian Ridge and Wocan field on the Carlsberg Ridge as two isolated populations prioritised for protection. Given its exceptional adaptations, wide distribution, and public recognition, the scaly-foot snail is well-positioned to serve as both a flagship and umbrella species to ensure the survival of a broader suite of vent biodiversity. As the International Seabed Authority finalises its Mining Code in 2025, our findings provide essential genomic evidence to mitigate the impacts of mining on genetic diversity and inform transboundary conservation strategies for this vulnerable ecosystem.

ecology↗

bioRxiv2025

Structure and iron-transporting mechanism of brain organic cation transporter 1

Brain organic cation transporter 1 (BOCT1), also known as the solute carrier family 22 member 17 (SLC22A17) or the receptor for lipocalin-2 (LCN2), plays critical roles in health and disease. Its deficiency in mice results in early postnatal mortality and severe neurogenesis impairments. Despite its importance in physiology and pathophysiology, BOCT1s structure and transport mechanism remain elusive. Here, we integrate cryo-electron microscopy (cryo-EM), functional assays, biochemical experiments, and molecular dynamics simulations to elucidate the structure, substrate recognition, and transport mechanism of mouse BOCT1 (mBOCT1). The high-resolution cryo-EM structure reveals a distinctive N-terminal domain with a unique folding pattern dominated by a transmembrane loop atop TM6 (TML6), diverging from both known structures of SLC22 transporters and AlphaFold predictions. Notably, mBOCT1 functions as a high-capacity, low-affinity iron transporter independent of LCN2 binding. Iron transport is facilitated by a substrate gating mechanism involving TML6. These findings establish a structural basis for BOCT1s role as an independent iron transporter, enhancing our understanding of the transport mechanisms within major facilitator superfamily (MFS) transporters and providing new insights into brain iron homeostasis.

biophysics↗

bioRxiv2025

Bridging Scales: Spectral Theory Reveals How Local Connectivity Rules Sculpt Global Neural Dynamics in Spatially Extended Networks

The brains diverse spatiotemporal activity patterns are fundamental to cognition and consciousness, yet how these macroscopic dynamics emerge from microscopic neural circuitry remains a critical challenge. We address this by developing a spatially extended neural network model integrated with a spectral theory of its connectivity matrix. Our theory quantitatively demonstrates how local structural parameters, such as E/I neuron projection ranges, connection strengths, and density determine distinct features of the eigenvalue spectrum, specifically outlier eigenvalues and a bulk disk. These spectral signatures, in turn, precisely predict the networks emergent global dynamical regime, encompassing asynchronous states, synchronous states, oscillations, localized activity bumps, traveling waves, and chaos. Motivated by observations of shifting cortical dynamics in mice across arousal states, our framework not only explains this repertoire of behaviors but also offers a principled approach to inferring underlying effective connectivity changes from macroscopic brain activity. By mechanistically linking neural structure to dynamics, this work provides a powerful tool for understanding brain function and paves the way for identifying potential biomarkers for neurological disorders.

biophysics↗

bioRxiv2025

BioMiner: A Multi-modal System for Automated Mining of Protein-Ligand Bioactivity Data from Literature

Protein-ligand bioactivity data published in the literature are essential for drug discovery, yet manual curation struggles to keep pace with rapidly growing literature. Automated bioactivity extraction remains challenging because it requires not only interpreting biochemical semantics distributed across text, tables, and figures, but also reconstructing chemically exact ligand structures (e.g., Markush structures). To address this bottleneck, we introduce BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW, a multi-modal extraction framework that explicitly separates bioactivity semantic interpretation from ligand structure construction. Within BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW, bioactivity semantics are inferred through direct reasoning, while chemical structures are resolved via a chemical-structure-grounded visual semantic reasoning paradigm, in which multi-modal large language models operate on chemically grounded visual representations to infer inter-structure relationships, and exact molecular construction is delegated to domain chemistry tools. For rigorous evaluation and method development, we further establish BO_SCPLOWIOC_SCPLOWVO_SCPLOWISTAC_SCPLOW, a comprehensive benchmark comprising 16,457 bioactivity entries curated from 500 publications. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW validates its extraction ability and provides a quantitative baseline, achieving an F1 score of 0.32 for bioactivity triplets. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOWs practical utility is demonstrated via three applications: (1) extracting 82,262 data from 11,683 papers to build a pre-training database that improves downstream models performance by 3.9%; (2) enabling a human-in-the-loop workflow that doubles the number of high-quality NLRP3 bioactivity data, helping 38.6% improvement over 28 QSAR models and identification of 16 hit candidates with novel scaffolds; and (3) accelerating protein-ligand complex bioactivity annotation, achieving a 5.59-fold speed increase and 5.75% accuracy improvement over manual workflows in PoseBusters dataset. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW and BO_SCPLOWIOC_SCPLOWVO_SCPLOWISTAC_SCPLOW provide a scalable extraction methodology and a rigorous benchmark, paving the way to unlock bioactivity data that previously required extensive human effort. All data and code are available at GitHub.

bioinformatics↗

bioRxiv2025

Deltex and RING-UIM E3 ligases cooperate to create a ubiquitin-ADP-ribose hybrid mark on tankyrase, promoting its stabilization

AbstractADP-ribosylation is a key post-translational modification that impacts diverse cellular pathways. The modification can occur as mono-ADP-ribose (MAR) or be extended into poly-ADP- ribose (PAR). Tankyrase, a PAR transferase, adds PAR to itself and other proteins to influence their function and stability by tagging them for proteasomal degradation via the PAR-binding E3 ligase RNF146. This degradation can be counteracted by RING-UIM E3 ligases RNF114 and RNF166, though the process is unclear. Here we identify a new mechanism that can regulate the balance between MAR and PAR on tankyrase to control degradation. We show that Deltex E3 ligases DTX2 and DTX3 catalyze monoubiquitylation of tankyrase in cells. This ubiquitylation occurs, not on a (canonical) lysine, but rather on mono-ADP-ribose, creating a monoubiquitin- MAR hybrid mark. RNF114 and RNF166 recognize this mark using a unique hybrid reader domain comprising two binding sites - one for MAR and one for ubiquitin - and further diubiquitylate it. This ubiquitylation of MAR, which occurs near the ADP-ribose addition site, prevents PAR formation, antagonizing the action of the PAR-binding E3 ligase RNF146 and stabilizing tankyrase. These findings reveal a novel interplay between ubiquitin, ADP-ribose, and E3 ligases in cellular signaling.

biochemistry↗

bioRxiv2025

Extracellular Nanobody Screening using Conformationally Stable GPCR

G protein-coupled receptors (GPCRs) are prominent drug targets that have attracted intensive efforts in drug screening. Binding-based screening methods for GPCR ligands often require conformationally stable, purified receptors. However, obtaining large quantities of GPCRs in stable states, particularly with unoccupied extracellular ligand-binding pockets and especially in their active conformations, remains challenging due to the inherent dynamic nature of these receptors. To address this challenge, we propose a universal approach for stabilizing GPCRs in specific conformations. Using the M1 muscarinic acetylcholine receptor (M1R) as a model, we successfully stabilized M1R in its active conformation through de novo design of a fusion protein. We screened a synthetic yeast display library of nanobodies against both the stabilized active-state and previously reported inactive-state M1R, identifying several nanobodies that specifically recognize each conformation. This method not only facilitates the stabilization of GPCRs in desired states but also provides valuable tools for developing more selective therapeutic agents, enhancing drug discovery efficiency and specificity.

biochemistry↗

bioRxiv2025

Iterative acylation on mature lasso peptides by widespread acetyltransferases for lipolasso production

The biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs) leverages iterative catalysis to enhance structural and biological diversity. Traditionally, iterative enzymes install multiple post-translational modifications (PTMs) on linear peptides, rather than mature RiPPs with intricate three-dimensional structures, which would require complex changes in substrate binding poses. Here, we present a prolific class of GCN5-related N-acetyltransferases (GNATs) that iteratively and consecutively acylate two Lys residues within the loop and ring motifs of lasso peptides, diverging from the typical iterative modification of linear peptides--an unprecedented function for PTM enzymes. Utilizing high-resolution cryo-electron microscopy and enzymatic reconstitution, we mapped the lasso peptide binding pocket of IatT and pinpointed key residues involved in demarcating the two distinct acetylation steps. Structure-based engineering of IatTs acetyl group recognition site expanded the cavity to accommodate longer-chain acyl groups, leading to the creation of lipolasso peptides, a novel class of ribosomal lipopeptide. This engineering strategy can be applied to any RiPP BGC encoding GNAT, facilitating the efficient diversification of rare ribosomal lipopeptides. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/630886v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d88af9org.highwire.dtl.DTLVardef@18c1298org.highwire.dtl.DTLVardef@118b9f3org.highwire.dtl.DTLVardef@580a50_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

Pan-cistrome analysis of the leaf accessible chromatin regions of 214 maize inbred lines

Characterizing the noncoding regions of the genome, particularly the cis-regulatory elements (CREs) located in accessible chromatin regions (ACRs) in gene promoters, is crucial for understanding how gene expression is regulated and how genotype contributes to phenotypic diversity in plants.In this study, we used ATAC-seq to resequence and map the ACRs of 214 maize inbred lines. We identified 82,174 ACRs and reported that 39.55% of them exhibited significant variation across the population. Next, we used the accessibility of ACRs as a quantitative feature and performed a chromatin associability GWAS (caGWAS), resulting in 27,004 caQTLs. Among them, 2,463 were predicted to disrupt the cis-regulatory elements that TF binds in these ACRs, suggesting that TF binding affects chromatin accessibility. Specifically, we identified two caACRs that regulate the expression of fad7, which encodes a fatty acid desaturase and affects the linolenic acid content.Our findings highlight the dynamic nature of maize ACRs and demonstrate that chromatin accessibility information could be used for GWASs, offering key insights into the genetic and regulatory mechanisms of chromatin accessibility and its impact on complex traits in plants.

genomics↗

bioRxiv2024

De novo Design of A Fusion Protein Tool for GPCR Research

G protein-coupled receptors (GPCRs) play pivotal roles in cellular signaling and represent prominent drug targets. Structural elucidation of GPCRs is crucial for drug discovery efforts. However, structural studies of GPCRs remain challenging, particularly for inactive state structures, which often require extensive protein engineering. Here, we present a de novo design strategy termed "click fusion" for generating fusion proteins to facilitate GPCR structural studies. Our method involves the rational design of structurally stable protein domains rigidly linked to GPCRs. The resulting fusion protein enhances the thermostability of the target GPCR and aids in determining GPCR structures via cryo-electron microscopy (cryo-EM). We further demonstrate that the designed fusion protein can be transferred among structurally similar GPCRs with minor adjustments to the linker region. Our study introduces a promising approach for facilitating GPCR structural studies and advancing drug discovery efforts.

biophysics↗

bioRxiv2024

Decreased Astrocytic CCL5 by MiR-324-5p Ameliorates Ischemic Stroke Injury via CCR5/ERK/CREB Pathway

Following ischemic stroke, Ccl5 mRNA expression increased, while miR-324-5p expression decreased in the peri-infarct cortex of middle cerebral artery occlusion (MCAO) mice. However, the roles of CCL5 and miR-324-5p in stroke remained largely unclear. Here, we show that inhibiting CCL5 using antibodies or miR-324-5p not only reduced infarct area and preserved neurological function in MCAO mice but also attenuated astrocyte reactivity and microglial activation, protected dendritic structures, and maintained spine density. In an astrocyte-neuron co-culture system after oxygen-glucose deprivation (OGD), inhibiting astrocytic CCL5 by antibody or miR-324-5p decreased neuronal apoptosis and preserved dendritic structure. Importantly, the suppression of CCL5 enhanced ERK/CREB pathway signaling both in vivo and in vitro. Consistent with these findings, the application of Maraviroc, a CCR5 antagonist, reduced infarct size, decreased neuronal apoptosis, and upregulated the ERK/CREB pathway in neurons treated with OGD. In conclusion, targeting the CCL5 pathway via miR-324-5p represents a promising therapeutic strategy for alleviating ischemic stroke damage through modulation of the neuronal CCR5/ERK/CREB pathway.

neuroscience↗

bioRxiv2024

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

Anti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, playing a pivotal role in cancer initiation and progression, as well as intrinsic or acquired resistance to therapy. Although inhibitors targeting BCL-2, such as Venetoclax, have shown efficacy in hematological malignancies, their therapeutic potential in solid tumors remains limited. Identifying novel molecular targets to overcome resistance to these inhibitors is of significant clinical importance. Here, we provide evidence of a strong synthetic lethality between WSB2, a previously underexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and anti-apoptotic BCL-2 family proteins. Mechanistically, WSB assembles a CRL5 E3 ubiquitin ligase complex that facilitates the ubiquitination and subsequent proteasomal degradation of NOXA, a pro-apoptotic BCL-2 family protein. Loss of WSB2 leads to a substantial accumulation of NOXA in both cultured cell lines and knockout mouse tissues. While WSB2 deficiency alone does not significantly impact spontaneous apoptosis, it sensitizes cells to apoptosis when anti-apoptotic BCL-2 family proteins are either genetically depleted or pharmacologically inhibited. Moreover, WSB2 is overexpressed in several human cancer types. These findings identify WSB2 as a critical regulator of mitochondrial apoptosis and reveal the dysregulation of the WSB2-NOXA axis as a key factor contributing to apoptosis resistance in cancer cells. Targeting both WSB2 and anti-apoptotic BCL-2 family proteins holds promising therapeutic potential for overcoming resistance in human cancers.

cell biology↗

bioRxiv2024

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCEMechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/583755v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@f07b60org.highwire.dtl.DTLVardef@33ef98org.highwire.dtl.DTLVardef@1b720c8org.highwire.dtl.DTLVardef@1c9514d_HPS_FORMAT_FIGEXP M_FIG Xie et al demonstrate that the polyploid giant cells (PGCs) in the juvenile phase expansion of female bone marrow mesenchymal stromal cells (fBMSCs) can boost neighboring cell proliferation for clonal expansion. However, when fBMSCs enter to the advanced-senescent phase, the dying-senescent PGCs form "spikings" which are then separated into membraned vesicles termed Senescent PGC spiking bodies, SPSBs). The SPSBs carrying fragmented mitochondrial elements and OXPHOS proteins can be phagocytosed by macrophage and breast epithelial cells leading to macrophage aging and breast epithelial protumorigenic transition. The SPSBs are demonstrated to be a new form of post-cell death vesicle from aging BMSCs and may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. C_FIG

cancer biology↗

bioRxiv2023

mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated non-degradative ubiquitination of eIF4A1

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies. Statement of Significance: Overexpression of IBTK contributes to the process of tumorigenesis by amplifying translation, and represents a promising target for anti-cancer therapies.

cancer biology↗