Biology subjects

Cui, B.

Publications and source records attributed to Cui, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Empathy and the Structural Representation of Facial Affect: Evidence from a Genetic-Algorithm Face Synthesis Task

Empathy has been linked to facial emotion recognition, but whether empathy is associated with the structural representation of facial affect (how observers position different affects relative to one another in face-shape space) remains largely unexplored. 53 adults completed a genetic-algorithm face task that generated prototypes for 13 affects using the Basel Face Model, and completed the 60-item Empathy Quotient (EQ). The genetic-algorithm task produced structurally distinct prototypes for all 13 affects (all paired tests p < .001 Bonferroni-corrected; Cohens dz 1.74-3.13), confirming that participants generated reliable, affect-specific face representations. A 13 x 13 between-affect distance matrix was then compared between higher-EQ (n = 30) and lower-EQ (n = 23) groups. 1 pair survived full correction across all 156 off-diagonal cells: Amusement x Contempt (Cohens d = -1.31), with higher-empathy participants representing these two affects as structurally closer to each other. Both amusement and contempt are social-evaluative affects that share overlapping facial action components, and this convergence may reflect heightened sensitivity to shared expressive structure among higher-empathy observers. In exploratory analyses, permutation testing and continuous-EQ correlations pointed to a broader pattern centered on social-evaluative affects (Amusement, Awe, Contempt, Fear, Happiness, Pride, Sadness, Interest). Individual differences in empathy appear most prominently associated with how social-evaluative affects are structurally positioned in face-shape space, suggesting that empathy modulates not just emotion recognition accuracy but the representational geometry of facial affect itself.

neuroscience↗

bioRxiv2026

Depression Severity Modulates the Cognitive Process of Facial Affect Representation: Evidence from a Genetic-Algorithm Face Synthesis Task

Depression is associated with biased facial emotion processing, yet existing paradigms measure only the recognition of pre-selected stimuli, conflating the process of forming an internal representation with its endpoint product. Here, we used a genetic-algorithm (GA) face synthesis task to disentangle these components. Fifty-seven undergraduates (40 Low Risk, 17 At Risk by Beck Depression Inventory-II) iteratively evolved photorealistic 3D faces to match their internal representations of 13 emotions across seven generations in a 199-dimensional face shape space. We extracted five evolutionary metrics capturing how participants constructed their representations (convergence speed, velocity, stability, range) and the structure they ultimately produced (peak intensity). At Risk participants converged on embarrassment representations significantly faster than Low Risk participants (d = 0.88, p = .001, FDR-corrected, permutation-validated), reaching their template in roughly half the number of generations. Anger representations showed greater evolutionary instability in the At Risk group (d = -0.75, p = .029, permutation-validated). Critically, endpoint face intensities did not differ between groups for any emotion. These results suggest that depression severity is associated with rigid self-conscious emotion schemas and unstable anger representations during face generation, reflecting altered cognitive processes rather than distorted perceptual products. The findings extend cognitive schema theory to the domain of facial affect representation and highlight self-conscious emotions as an underexplored locus of depression-related perceptual bias.

neuroscience↗

bioRxiv2026

Beyond forced choice: hyper-realistic AI faces reveal a four-cluster perceptual geometry of emotion

Forced-choice paradigms in facial emotion perception research require observers to commit to a single label and discard any simultaneous activation of related categories that participants might otherwise express. We introduce a multi-select rating paradigm in which 112 participants rated each of 52 facial-expression stimuli on 13 emotion categories using continuous 0-to-10 sliders, alongside a separate authenticity slider. Stimuli were generated using OpenAIs DALL-E 3 from an orthogonal four-factor design (emotion, race, gender, age), allowing demographic balance and compositional uniformity more readily than photograph-based stimulus sets permit. Linear mixed-effects models with participant random intercepts and logistic regression with cluster-robust standard errors were applied to 5,824 trials. Perceived authenticity reliably predicted agreement between the participants top-rated category and the AI-prompted target emotion (odds ratio 1.03 per +1 unit, p < .001), and a principal-components analysis of the 13-emotion rating matrix recovered three interpretable dimensions accounting for over half of trial-level variance, with the first two corresponding to the canonical valence and arousal axes. Hierarchical clustering exposed a tight cluster of self-conscious negative emotions (sadness, embarrassment, shame) that does not align with the canonical basic-versus-complex emotion distinction. Collapsing the participants top-rated emotion to its cluster raised the trial-level prompt-agreement rate from 43.1% to 86.9% ({Delta} = +43.8 percentage points), indicating that participants most common departures from the prompted target fell within rather than across clusters. Among Autism-Spectrum Quotient subscales, the Social-Skill subscale showed a robust interaction with contempt-target faces (p < .001), with higher Social-Skill scores predicting elevated contempt ratings of approximately 1.2 points on the 0-to-10 scale. Two further secondary patterns emerged in the AQ-subscale-by-emotion grid, including an opposing-direction effect of Imagination and Attention-to-Detail subscales on awe ratings. We acknowledge that some of the recovered structure may partly reflect statistical regularities of the AI-generation pipeline rather than human perceptual geometry alone, and we discuss this caveat at length below. Multi-select rating with hyper-realistic AI-generated stimuli produces a richer perceptual probe than the forced-choice paradigms that have dominated this literature, and reveals subscale-level autistic-trait associations that AQ-total analyses obscure.

neuroscience↗

bioRxiv2026

Cryo-EM elucidation of stoichiometric plasticity, asymmetric ligand recognition and allosteric coupling in human P2X2/3 heterotrimeric channels

P2X receptors are trimeric ATP-gated ion channels that assemble as homo- or heterotrimers, with heteromeric forms exhibiting intrinsic asymmetry that influences function. Here, we report four high-resolution cryo-EM structures of human P2X2/3 heterotrimers representing distinct functional states, including ATP-bound assemblies (P2X332 and P2X223), the apo form, and a ligand/ATP-bound closed conformation. The three ATP-binding sites show asymmetric recognition of MgATP{superscript 2}- and ATP-, and channel activation requires occupancy of only two MgATP{superscript 2}- molecules. Gefapixant binds a single allosteric site and selectively inhibits MgATP{superscript 2}-, but not ATP-, binding, indicating orthosteric-allosteric coupling within the heterotrimer. Structural features of the transmembrane domain define ion permeation, particularly for Ca{superscript 2}. Despite asymmetric ligand interactions, gating remains largely symmetric, with minor differences in desensitization. These findings provide a structural framework linking asymmetry to coordinated channel function and open avenues for subtype-selective therapeutic intervention.

biophysics↗

bioRxiv2026

Membrane Curvature Activates Src kinase and Promotes Metastatic Cancer Cell Survival

Src family kinases (SFKs) play key roles in cancer metastasis. While SFKs are classically regulated by cell adhesions and transmembrane receptors, how they become activated following tumor cell detachment remains unclear. Here, we report curvature-induced kinase activation (CIKA), a distinct mechanism through which plasma membrane curvature directly promotes Src activation. Mechanistically, membrane curvature promotes the oligomerization of TOCA-family curvature-sensing proteins, inducing local biomolecular condensation. These condensates recruit Src, stabilize its open conformation, and exclude the negative regulator Csk, converting curved membrane domains into discrete kinase activation hubs. Disruption of CIKA using TOCA mutants inhibits curvature-induced Src activation and selectively impairs the viability of detached but not adherent cells. Functionally, curvature-induced Src activation promotes anchorage-independent survival, and its disruption suppresses metastatic colonization in xenograft mouse models. These findings reveal membrane curvature as a biophysical activator of Src and suggest CIKA inhibition as a potential therapeutic strategy to target metastatic cancer cells.

cell biology↗

bioRxiv2026

Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces

Natural Killer(NK) cells eliminate target cells through antibody-dependent cell-mediated cytotoxicity(ADCC), initiated by CD16a(Fc{gamma}RIIIa) recognizing the Fc region of antibodies bound to the target cell surface. While the recognition is considered to be driven by CD16a-Fc binding avidity, it fails to explain why Fc multimers inhibit ADCC rather than trigger it. Here, we reveal that CD16a transduces piconewton forces, and acts as a mechanosensor to facilitate NK activation. We demonstrate that CD16a force and the actin foci formation associated with it are essential for the phosphorylation of mechanosensitive adaptor Cas-L and signaling adaptor LAT, reshaping NK cell cytoskeletal dynamics and signaling. Our findings show that NK activation is an intricate process that integrates both biochemical and biophysical information, and provides new mechanistic insight for immunoengineering.

biophysics↗

bioRxiv2025

FCHo2, instead of talin, enables inside-out activation of integrin αvβ5 in curved adhesions

Inside-out activation of integrins is crucial for transducing mechanical forces through the extracellular ligand-integrin-talin-F-actin axis. Extensive studies have shown that talin is the essential player in this process by binding to the intracellular tail of {beta} integrins. Here, we show that, while talin binding is essential for inside-out integrin activation in focal adhesions, it is dispensable in curved adhesions - a distinct adhesion architecture that is exclusively mediated by integrin v{beta}5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in the cytoplasmic tail of integrin {beta}5 (ITG{beta}5) and inside-out activates integrin v{beta}5 in curved adhesions. Intriguingly, FCHo2 does not bind to a similar motif in the homologous integrin {beta}3 tail. Through truncations and mutations, we identified a pivotal tryptophan (W) in the {beta}3 tail, which is conserved in all homologous integrin {beta} isoforms except {beta}5, where it is replaced by a tyrosine (Y766). This tyrosine substitution is crucial for integrin {beta}5s unique capability in forming curved adhesions. A Y766W mutation abolishes integrin {beta}5s capacity to form curved adhesions, without affecting its ability to form focal adhesions. Furthermore, our studies suggest that the phosphorylation state of Y766 regulates whether integrin v{beta}5 forms curved adhesions or focal adhesions, providing a cellular mechanism governing different adhesion types. Overall, our work unveils distinct molecular interactions and regulatory mechanisms between curved adhesions and focal adhesions, and establishes a molecular basis for the formation of curved adhesions by integrin v{beta}5. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/691229v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@eb4addorg.highwire.dtl.DTLVardef@1802a01org.highwire.dtl.DTLVardef@145e805org.highwire.dtl.DTLVardef@83d641_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

The Contextual Affects of Facial Expression

Affect recognition and communication are critical for everyday social interaction. Traditional emotion research has often assumed that facial expressions reliably reflect internal emotional states and conform to a set of universal expressions. However, emerging evidence suggests that facial expressions are highly individualized and influenced by context. Recent work using genetic algorithms (GAs) has revealed profound individual differences in internal representations of emotion, but these studies have not examined how contextual information modulates such representations. To investigate the joint effects of context and individual differences, we used GAs to enable 12 participants to generate personalized facial expressions matching their subjective interpretation of affect within written contextual scenarios. Standardized scenarios drawn from Howard Schatzs Actors Acting were independently rated across 13 primary emotions. In the MAX condition, each primary emotion was paired with a scenario maximizing a secondary emotion; in the MIN condition, the secondary emotion was minimized; in the WORD condition, participants selected faces based on emotion words alone. Faces were generated within the 199-dimensional shape coefficient space of the Basel Face Database across 6 generations per trial. We found a significant main effect of condition on selection rate (p < .001), with participants selecting more faces under contextual conditions than under WORD. Critically, context differentially modulated specific emotions: Embarrassment, Surprise, and Disgust showed large context effects (all p < .001), whereas Sadness, Awe, and Anger did not. Cosine distance analysis confirmed that face clusters were emotion-specific (d = -7.88) and that their separation varied with context. The GA showed robust convergence across generations (d = 0.61). Strong individual differences were observed (2 = .229), with low inter-participant agreement (mean r = .06). These results support constructionist models of emotion by demonstrating that facial expression representations are context-dependent, with context selectively modulating certain emotions more than others.

neuroscience↗

bioRxiv2025

The Affects of Central Vision Loss on Emotion Perception

Central vision loss (CVL) from age-related macular degeneration (AMD) profoundly impacts daily life. While much research focuses on visual discrimination and reading, understanding how CVL affects emotional perception remains unexplored. We adapted the genetic-algorithm face paradigm introduced by Carlisi et al. (2021) and extended by Binetti et al. (2022), combining it with a three-dimensional morphable face model, to investigate how healthy young, healthy older, and CVL-affected individuals internally represent facial emotions. Participants evolved faces they perceived to best express 13 distinct emotions (or 4 for the older healthy group). Using a three-cohort design, we separated age effects from CVL-specific effects. Results revealed four significant group differences: Awe Convergence (H = 10.97, p = 0.001), Shame Intensity (H = 10.04, p = 0.005), Interest Range (H = 6.35, p = 0.016), and Interest Stability (H = 4.86, p = 0.026). Additionally, cosine similarity analysis in 199-dimensional face space showed cohorts use fundamentally different facial feature configurations (mean cosine {approx}0.006 for YNG vs CVL), suggesting CVL may reorganize emotion representations rather than simply scaling them. These preliminary findings raise questions about whether all emotions require uniform amplification in CVL and point toward the potential value of selective rehabilitation over broad caricaturing approaches.

neuroscience↗

bioRxiv2025

EPAS1 regulates host antibacterial defense in response to bacterial quorum sensing

Hypoxia-inducible factors (HIFs) are a family of transcription factors that function as sensors of hypoxia. However, it remains unclear whether and how HIFs modulate host immunity by responding to other ligands. Here, we describe an immune regulatory function of HIF-2 (also known as EPAS1) in response to cis-2-dodecenoic acid (BDSF), a quorum sensing (QS) signal, secreted by Burkholderia cenocepacia. Upon ligand binding, EPAS1 activation leads to the production of inflammatory cytokines and the initiation of antibacterial defense. Inoculation with diffusible BDSF or liposome-encapsulated BDSF improves survival in mice infected with B. cenocepacia or Acinetobacter baumannii by preconditioning the immune system. Our findings reveal a previously unidentified role of EPAS1 as an intracellular pattern recognition receptor (PRR) for bacterial QS signal to control host antibacterial defense.

microbiology↗

bioRxiv2025

HIV-1 Infection Regulates Gene Expression by Altering Alternative Polyadenylation Through CPSF6 and CPSF5 Delocalization

HIV-1 viral core transport to the nucleus, an early infection event, triggers cleavage and polyadenylation specificity factor (CPSF)5 and CPSF6 to translocate from paraspeckles to nuclear speckles, forming puncta-like structures. CPSF5 and CPSF6 regulate alternative polyadenylation (APA), which governs approximately 70% of gene expression. APA alters the lengths of mRNA 3-untranslated regions (3-UTRs), which contain regulatory signals influencing RNA stability, localization, and function. We investigated whether HIV-1 infection-induced changes in CPSF5 and CPSF6 subcellular localization are accompanied by changes in cellular function. Using two independent methodologies to assess APA in human primary CD4+ T cells and cell lines, we found that HIV-1 infection regulates APA, dependent on the interaction of CPSF6 with the viral capsid, recapitulating the APA phenotype observed in CPSF6 knockout cells. Our study demonstrates that HIV-1 infection leverages the interaction between the viral capsid and CPSF6 to co-opt cellular processes, alter gene expression, and drive pathogenesis.

microbiology↗

bioRxiv2025

Auto-downregulation of the florigen FT production prevents precocious flowering in plants

In many flowering plants, the developmental switch from vegetative growth to reproduction (flowering) is timed by seasonal changes in the length of daylight (photoperiod). Under inductive day lengths, the photoperiod pathway typically generates rhythmic expression of a transcriptional activator for florigen production. In the facultative long-day plant Arabidopsis thaliana, long-day exposure results in increasing buildup of the CONSTANS (CO) protein towards the end of daylight, and CO activates the expression of the major florigen gene FLOWERING LOCUS T (FT) to confer long-day induction of flowering. CO-mediated FT activation must be properly controlled to prevent an excessive florigen production and precocious flowering under inductive long days, but the underlying mechanism remains elusive. Here, we report an auto-repression mechanism to prevent excessive FT production in inductive photoperiods. We show that the transcription factor FD is expressed in leaf veins and complexes with FT to recognize several cis-regulatory DNA motifs in FT promoter. FT-FD antagonizes CO-mediated FT activation to feedback down-regulate FT expression and thus prevent its excessive induction by long-day signals, thereby precluding precocious transition to flowering. Furthermore, we found that in the facultative short-day plant soybean, an FT homolog directly represses its own expression. Thus, the auto-repression of FT or an FT homolog is a conserved mechanism to prevent excessive production of this potent floral regulator in plants, ensuring the floral transition at a proper time to balance vegetative growth with reproductive success and maximize plant production.

plant biology↗

bioRxiv2025

Targeting Non-Catalytic Sites of SRC Sensitizes the Efficacy of SRC Kinase Inhibitors in Solid Tumors

The non-receptor tyrosine kinase SRC promotes the progression of hematologic malignancies and numerous solid tumors. Several SRC kinase inhibitors have been approved for the treatment of hematologic malignancies. However, drug resistance to sole ATP pocket-targeted kinase inhibition, coupled with low potency for solid tumors and insufficient selectivity, has limited the clinical application of SRC kinase inhibitors. The non-catalytic functions of kinases have provided crucial mechanisms underlying kinase inhibitor resistance, thereby presenting new opportunities for discovery SRC-targeted strategies. In this study, we discovered that upon abrogation of phosphorylation by SRC kinase inhibitors, non-catalytic SRC promotes the transcription of the oncogenes TRIB3 and SPC24 transcription by binding to their promoter sequence. Simultaneously, it interacts with TRIB3 and prevents their proteasome-mediated degradation by the E3 ligase CHIP, ultimately inducing resistance to SRC kinase inhibitors. The peptide TS1-2, blocking SRC/TRIB3 interaction in non-catalytic regions, inhibits the tumor progression of pancreatic ductal adenocarcinoma (PDAC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and breast invasive carcinoma (BRCA), and enhances the efficacy of SRC kinase inhibitors in solid tumors. This study provides the insights of non-catalytic functions of SRC, validates the tumor-promoting function and mechanism of nuclear accumulation of SRC/TRIB3 following SRC kinase inhibitor treatment, identifies SRC/TRIB3 interaction as a potential non-catalytic target, and offers the candidate peptide TS1-2 as a potential combination strategy for overcoming SRC kinase inhibitor resistance. SignificanceThe scaffolding functions of SRC reduced the efficacy of SRC kinase inhibitors, and targeting SRC/TRIB3 non-catalytic functions synergizes the therapeutic effects of SRC kinase inhibitors in SRC-dependent solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/638389v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@17aa618org.highwire.dtl.DTLVardef@12e86eeorg.highwire.dtl.DTLVardef@19c8d82org.highwire.dtl.DTLVardef@10e6c46_HPS_FORMAT_FIGEXP M_FIG C_FIG SRC kinase inhibitors block myristoylation-dependent membrane location and catalytic phosphorylation of SRC. Phosphorylated SRC activates STAT1 and thereby represses TRIB3 transcription. Accumulated non-catalytic SRC promotes TRIB3, SPC24 transcription. Upregulated TIRB3 interacts with SRC to reduce CHIP-mediated ubiquitin-proteasomal degradation. The peptide TS1-2 disrupts TRIB3/SRC complex by targeting Non-kinase regions of SRC, consequently enhancing the therapeutic efficacy of SRC kinase inhibitors.

cancer biology↗

bioRxiv2024

Assembloid model to study loop circuits of the human nervous system

Neural circuits connecting the cerebral cortex, the basal ganglia and the thalamus are fundamental networks for sensorimotor processing and their dysfunction has been consistently implicated in neuropsychiatric disorders1-9. These recursive, loop circuits have been investigated in animal models and by clinical neuroimaging, however, direct functional access to developing human neurons forming these networks has been limited. Here, we use human pluripotent stem cells to reconstruct an in vitro cortico-striatal-thalamic-cortical circuit by creating a four-part loop assembloid. More specifically, we generate regionalized neural organoids that resemble the key elements of the cortico-striatal-thalamic-cortical circuit, and functionally integrate them into loop assembloids using custom 3D-printed biocompatible wells. Volumetric and mesoscale calcium imaging, as well as extracellular recordings from individual parts of these assembloids reveal the emergence of synchronized patterns of neuronal activity. In addition, a multi-step rabies retrograde tracing approach demonstrate the formation of neuronal connectivity across the network in loop assembloids. Lastly, we apply this system to study heterozygous loss of ASH1L gene associated with autism spectrum disorder and Tourette syndrome and discover aberrant synchronized activity in disease model assembloids. Taken together, this human multi-cellular platform will facilitate functional investigations of the cortico-striatal-thalamic-cortical circuit in the context of early human development and in disease conditions.

neuroscience↗

bioRxiv2024

Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with the nuclear speckle

Viruses rely on host cellular machinery for replication. After entering the nucleus, the HIV genome accumulates in nuclear niches where it undergoes reverse transcription and integrates into neighboring chromatin, promoting high transcription rates and new virus progeny. Despite antiretroviral treatment, viral genomes can persist in these nuclear niches and reactivate upon treatment interruption, raising the possibility that they could play a role in the establishment of viral reservoirs. The post-nuclear entry dynamics of HIV remain unclear, and understanding these steps is critical for revealing how viral reservoirs are established. In this study, we elucidate the formation of HIV-induced CPSF6 puncta and the domains of CPSF6 essential for this process. We also explore the roles of nuclear speckle scaffold factors, SON and SRRM2, in the biogenesis of these puncta. Through genetic manipulation and depletion experiments, we demonstrate the key role of the intrinsically disordered region of SRRM2 in enlarging nuclear speckles in the presence of the HIV capsid. We identify the FG domain of CPSF6 as essential for both puncta formation and binding to the viral core, which serves as the scaffold for CPSF6 puncta. While the low-complexity regions (LCRs) modulate CPSF6 binding to the viral capsid, they do not contribute to puncta formation, nor do the disordered mixed charge domains (MCDs) of CPSF6. Interestingly, the FG peptide facilitates viral replication. These results demonstrate how HIV evolved to hijack host nuclear factors, enabling its persistence in the host. Of note, this study provides new insights into the underlying interactions between host factors and viral components, advancing our understanding of HIV nuclear dynamics and offering potential therapeutic targets for preventing viral persistence. HighlightsO_LIThe formation of HIV-induced CPSF6 puncta is critical for restoring HIV-1 nuclear reverse transcription. C_LIO_LICPSF6 protein lacking the FG peptide cannot bind to the viral core, thereby failing to form HIV-induced CPSF6 puncta. C_LIO_LIThe FG peptide, rather than low-complexity regions (LCRs) or the mixed charge domains (MCDs) of the CPSF6 protein, drives the formation of HIV-induced CPSF6 puncta. C_LIO_LIThe presence of the FG peptide plays a pivotal role in facilitating viral replication within macrophage-like cells. C_LIO_LIHIV-induced CPSF6 puncta form individually and later fuse with nuclear speckles (NS) via the intrinsically disordered region (IDR) of SRRM2. C_LI

microbiology↗

bioRxiv2024

Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of Alpha-Synuclein and Restores Impaired Mitochondrial Function

Membrane binding and aggregation properties of -synuclein are closely associated with Parkinsons disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating -synuclein interaction with the lipid membranes and mitigating impairment of mitochondrial function induced by -synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminus acetylated -synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy (TEM) showed that SS-31 inhibits membrane-induced -synuclein aggregation and alters the morphology of -synuclein fibrils. Moreover, Seahorse Mito Stress Test indicated that SS-31 restores impaired mitochondrial function in -synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of -synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings underscore the multifaceted protective role of SS-31 against mitochondrial dysfunction caused by -synuclein aggregation. Consequently, SS-31 emerges as a promising therapeutic candidate to attenuate neurodegeneration pertinent to -synuclein misfolding and aggregation. There is a good potential for further refinement of such peptide against many diseases linked to mitochondrial dysfunction and oxidative stress.

biochemistry↗

bioRxiv2024

Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

cell biology↗

bioRxiv2024

The long-chain fatty acid-CoA ligase FadD1 monitors Pseudomonas aeruginosa quorum sensing as a receptor of cis-2-decenoic acid

Diffusible signal factor (DSF)-family quorum sensing (QS) signals are widely utilized by many bacterial pathogens to modulate various biological functions and virulence. Previous studies showed that cis-2-decenoic acid (cis-DA) is involved in modulation of biofilm dispersion in Pseudomonas aeruginosa, but its signaling mechanism remains vague. Here, we report that cis-DA regulates the physiology and virulence of P. aeruginosa through the long-chain fatty acid-CoA ligase FadD1. Cis-DA specifically binds to FadD1 with high affinity and enhances the binding of FadD1 to the promoter DNA region of lasR. Further analysis showed that the FadD1 is a response regulator of cis-DA with a DNA-binding leucine zipper motif to control the transcription of various target genes. Moreover, FadD1 exhibited catalytic activity on cis-2-dodecenoic acid (BDSF) of Burkholderia cenocepacia and enhanced the competitiveness of P. aeruginosa. Together, our work presents a new DSF-type QS signaling system, which is highlighted by its receptor and response regulator evolved from a canonical enzyme of fatty acid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/598097v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@66b8aaorg.highwire.dtl.DTLVardef@1e5b9b9org.highwire.dtl.DTLVardef@1043525org.highwire.dtl.DTLVardef@13d3ed1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsThe long-chain fatty acid-CoA ligase FadD1 acts as a global transcriptional regulator in P. aeruginosa. FadD1 is a receptor of QS signal cis-DA and functions at the top of the QS hierarchy in P. aeruginosa. The homolog of FadD1 in P. fluorescens could bind to the target gene promoter by responding to cis-DA. In briefPseudomonas aeruginosa is a human pathogen with antibiotic resistance and a wide range of dynamic defenses makes it an extremely challenging organism to treat in modern-day medicine. It employs cis-2-decenoic acid (cis-DA) quorum sensing to regulate the physiology and pathogenesis. Song et al. demonstrate that the long-chain fatty acid-CoA ligase FadD1 controls the important biological functions and virulence in P. aeruginosa as a novel response regulator of cis-DA signal.

microbiology↗