Biology subjects

Liu, Y.-W.

Publications and source records attributed to Liu, Y.-W..

12 recordsLinked to original sources

bioRxiv2026

Infection-Induced Dynamin-2 Repurposing Drives Podosome Maturation and Mechanical Immunity

Macrophages are the vanguard of innate immunity, relying on phagocytosis to clear invading pathogens. Podosomes in macrophages have recently emerged as mechanical structures that assemble at phagocytic cups to facilitate pathogen clearance. However, how these unique actin structures are regulated to execute antimicrobial functions remains poorly understood. Here, we reveal that fungal infection drives podosome maturation to strengthen macrophage mechanical immunity. Exposure to the opportunistic fungus Candida albicans upregulates the scaffold protein Tks5 and activates Src kinase, which repurposes dynamin-2 from a membrane fission enzyme into an actin-bundling protein. This functional switch stabilizes the podosome actin core, enhancing the adhesion and mechanical force generation required to efficiently engulf, fold, and trap invading fungi. Ultimately, our findings define a mechanobiological paradigm in which infection-induced molecular repurposing drives macrophage antifungal immunity.

cell biology↗

bioRxiv2026

Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota

We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.

immunology↗

bioRxiv2025

Targeting Putrescine Homeostasis with Lactiplantibacillus plantarum PS128 to Mitigate Autism-like Behaviors in Fmr1 KO Mice

BackgroundAutism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic Lactiplantibacillus plantarum PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout (Fmr1 KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors. ResultsWe found that autism-like behaviors in Fmr1 KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine-ornithine-polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in Fmr1 KO mice. ConclusionsThese findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine-ornithine-polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut-brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD. Graphical AbstractWe identify dysregulated microbiota-driven polyamine homeostasis as a causal contributor to autism-like behaviors in Fmr1 knockout mice. A psychobiotic intervention restores gut-brain metabolic balance and rescues social and repetitive behavioral deficits through coordinated microbial and host transport regulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/694366v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@e1e780org.highwire.dtl.DTLVardef@125a3baorg.highwire.dtl.DTLVardef@201228org.highwire.dtl.DTLVardef@1880650_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

The PXBAR-domain protein SNX9 selectively sequesters PI(3,4)P2 lipid and protects it from hydrolysis at the plasma membrane

Plasma membrane remodeling processes are tightly regulated by the spatiotemporal distribution and dynamic conversion of phosphoinositidyl lipids (PIPs). This regulation is controlled by the recruitment of proteins such as sorting nexin 9 (SNX9), a key mediator of late-stage endocytosis and macropinocytosis. Using live cell imaging, in vitro reconstitution assays, and molecular dynamics simulations, we investigated how SNX9 distinguishes between PI(3,4)P2 and PI(4,5)P2, and the physiological relevance of this selectivity. Our results revealed that during macropinocytic membrane ruffling, SNX9 is recruited in a spatiotemporally coordinated manner with PI(3,4)P2, but not with PI(4,5)P2. While SNX9 induces comparably weak mechanical remodeling on model membranes containing either PIP2 species, it exhibits a clear selective binding to PI(3,4)P2, mediated by a non-canonical interface. Through mutational analysis of key residues involved in this sequestration, we further demonstrated that SNX9 protects PI(3,4)P2 from hydrolysis. Together, these results reveal a previously unrecognized mechanism of SNX9-PIP2 lipid interaction that underscores SNX9s pivotal role in coordinating membrane remodeling processes. TeaserCurvature sensing BAR protein SNX9 selectively sequesters PI(3,4)P2 lipids, acting as a checkpoint in cell membrane remodeling.

biophysics↗

bioRxiv2024

Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8+ T cell pathogenicity in non-obese diabetic mice

Our understanding of autoimmune diabetes underscores the critical involvement of CD8+ T cells recognizing islet-specific antigens. However, the influence of thymic positive selection on diabetogenic CD8+ T cell development remains unclear. Using CD5 marker representing T-cell receptor (TCR) signal strength, we illustrated that naive CD5hiCD8+ T cells of non-obese diabetic (NOD) mice with enhanced TCR signals displayed predisposed differentiated/memory T cell traits with increased activation and proliferation upon TCR stimulation, compared to CD5lo counterparts. Additionally, CD5hiCD8+ T cells exhibited gene expression landscape similar to effector T cells and exacerbated disease in transfer model. Interestingly, the protective effects of transgenic phosphatase Pep expression, which lowers TCR signaling and diabetes incidence, were abolished in NOD strain 8.3 with high CD5 expression linked to increased thymic positive selection. Strikingly, TCR repertoire analysis identified higher frequencies of autoimmune disease-related clonotypes in naive CD5hiCD8+ cells, supporting that distinct effector functions arise from intrinsic TCR repertoire differences. Overall, CD5hiCD8+ clones may be potential targets for autoimmune diabetes treatment.

immunology↗

bioRxiv2022

The anti-platelet drug cilostazol enhances interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

RationaleCilostazol, an anti-platelet phosphodiesterase-3 inhibitor used for the treatment of intermittent claudication, is known for its pleiotropic effects on platelets, endothelial cells and smooth muscle cells. However, how cilostazol impacts the endocrine system and the injury-induced inflammatory processes remains unclear. MethodsWe used the zebrafish, a simple transparent model that demonstrates rapid development and a strong regenerative ability, to test whether cilostazol influences steroidogenesis, and the temporal and dosage effects of cilostazol on innate immune cells during tissue damage and repair. ResultsWhile dosages of cilostazol from 10 to 100 M did not induce any noticeable morphological abnormality in the embryonic and larval zebrafish, the heart rate and adrenal/interrenal steroidogenesis in larval zebrafish was increased in a dose-dependent manner. During larval fin amputation and regeneration, cilostazol treatments did not affect the immediate injury-induced recruitment of either neutrophils or macrophages, followed by a subtle yet significant effect on reducing the neutrophil retention at the lesion site. ConclusionsOur results indicate that cilostazol has a significant effect on the growth and endocrine function of steroidogenic tissue; and a limited effect on the neutrophil retention without affecting neutrophil and macrophage recruitment during tissue damage and repair.

pharmacology and toxicology↗

bioRxiv2021

Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

cell biology↗

bioRxiv2021

Evolving in the darkness: phylogenomics of Sinocyclocheilus cavefishes highlights recent diversification and cryptic diversity

Troglomorphism-- any morphological adaptation enabling life to the constant darkness of caves, such as loss of pigment, reduced eyesight or blindness, over-developed tactile and olfactory organs--has long intrigued biologists. However, inferring the proximate and ultimate mechanisms driving the evolution of troglomorphism in freshwater fish requires a sound understanding of the evolutionary relationships between surface and troglomorphic lineages. We use Restriction Site Associated DNA Sequencing (RADseq) to better understand the evolution of the Sinocyclocheilus fishes of China. With a remarkable array of derived troglomorphic traits, they comprise the largest cavefish diversification in the world, emerging as a multi-species model system to study evolutionary novelty. We sequenced a total of 120 individuals throughout the Sinocyclocheilus distribution. The data comprised a total of 646,497bp per individual, including 4378 loci and 67,983 SNPs shared across a minimum of 114 individuals at a given locus. Phylogenetic analyses using either the concatenated RAD loci (RAxML) or the SNPs under a coalescent model (SVDquartets, SNAPP) showed a high degree of congruence with similar topologies and high node support (> 95 for most nodes in the phylogeny). The major clades recovered conform to a pattern previously established using Sanger-based mt-DNA sequences, with a few notable exceptions. We now recognize six major clades in this group, elevating the blind cavefish S. tianlinensis and the micro-eyed S. microphthalmus as two new distinct clades due to their deep divergence from other clades. PCA plots of the SNP data also supports the recognition of six major clusters of species congruent with the identified clades based on the spatial arrangement and overlap of the species in the PC space. A Bayes factor delimitation (BFD) analysis showed support for 21 species, recognizing 19 previously described species and two putative new cryptic ones. Two species whose identities were previously disputed, S. furcodorsalis and S. tianeensis, are supported here as distinct species. In addition, our multi-species calibrated tree in SNAPP suggests that the genus Sinocyclocheilus originated around 10.5 Mya, with most speciation events occurring in the last 2 Mya, likely favored by the uplift of the Qinghai-Tibetan Plateau and cave occupation induced by climate-driven aridification during this period. These results provide a firm basis for future comparative studies on the evolution of Sinocyclocheilus and its adaptations to cave life.

evolutionary biology↗

bioRxiv2021

Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3a-Dyn2-Bin1 Interplay

Insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3 or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.

cell biology↗

bioRxiv2020

Dynamin-2 regulates synaptic podosome maturation to facilitate neuromuscular junction development

Neuromuscular junctions (NMJs) govern rapid and efficient neuronal communication with muscle cells, which relies on the proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to elaborate NMJ development has been unclear. In this study, we reveal that the GTPase dynamin-2 (Dyn2), best-known for catalyzing synaptic vesicle endocytosis at the presynaptic membrane, is also involved in postsynaptic morphogenesis. We demonstrate that Dyn2 is enriched in the postsynaptic membrane of muscle cells and is involved in the maturation of neurotransmitter receptor clusters via its actin bundling ability. Dyn2 functions as a molecular girdle to regulate synaptic podosome turnover and promote morphogenesis of the postsynaptic apparatus. In Drosophila NMJs, Dyn2 is required to organize the postsynaptic actin cytoskeleton and to mediate its electrophysiological activities. Mechanistically, the actin binding, self-assembly, GTP hydrolysis ability, and Y597 phosphorylation of Dyn2 all regulate its actin bundling activity. Together, our study uncovers a role for Dyn2 in cytoskeleton remodeling and organization at the postsynaptic membrane of NMJs.

molecular biology↗

bioRxiv2020

Evolution in Sinocyclocheilus cavefish is marked by rate shifts, reversals and origin of novel traits

Epitomized by the well-studied Astyanax mexicanus, cavefishes provide important model organisms to understand adaptations in response to divergent natural selection. However, the spectacular Sinocyclocheilus diversification of China, the most diverse cavefish clade in the world harboring nearly 75 species, demonstrate evolutionary convergence for many traits, yet remain poorly understood in terms of their morphological evolution. Here, using a broad sample of 49 species representative of this diversification, we analyze patterns of Sinocylocheilus evolution in a phylogenetic context. We categorized species into morphs based on eye-related condition: Blind, Micro-eyed (small-eyed), and Normal-eyed and we also considered three habitat types (Troglodytic - cave-restricted; Troglophilic - cave-associated; Surface - outside of caves). Geometric morphometric analyses show Normal-eyed morphs with fusiform shapes being segregated from Blind/Micro-eyed (Eye-regressed) morphs with deeper bodies along the first principal component ("PC") axis. The second PC axis accounts for shape complexity related to the presence of horns. Ancestral character reconstructions of morphs suggest at least three independent origins of Blind morphs, each with different levels of modification in relation to the typical morphology of ancestral Normal-eyed morphs. Interestingly, only some Blind or Micro-eyed morphs bear horns and they are restricted to a single clade (Clade B) and arising from a Troglodytic ancestral species. Our geophylogeny shows an east-to-west diversification spanning the Pliocene and the Pleistocene, with Troglodytic species dominating karstic subterranean habitats of the plains whereas predominantly Surface species inhabit streams and pools in hills to the west (perhaps due to the scarcity of caves). Integration of morphology, phylogeny and geography suggests Sinocyclocheilus are pre-adapted for cave dwelling. Analyses of evolutionary rates suggest that lineages leading to Blind morphs were characterized by significant rate shifts, such as a slowdown in body size evolution and a 3.3 to 12.5 fold increase in the evolutionary rate of eye regression. Furthermore, body size and eye size have undergone reversals, but horns have not, a trait that seem to require substantial evolutionary time to form. These results, compared to the Astyanax model system, indicate Sinocyclocheilus fishes demonstrate extraordinary morphological diversity and variation, offering an invaluable model system to explore evolutionary novelty.

evolutionary biology↗

bioRxiv2019

Acute decrease in plasma membrane tension induces macropinocytosis via PLD2 activation

Internalization of macromolecules and membrane into cells through endocytosis is critical for cellular growth, signaling, and membrane tension homeostasis. Although endocytosis is responsive to both biochemical and physical stimuli, how physical cues modulate endocytic pathways is less understood. In contrary to the accumulating discoveries on effects of increased membrane tension on endocytosis, little is known about how a drop of tension impacts membrane trafficking. Here we reveal that acute reduction of plasma membrane tension results in phosphatidic acid, F-actin and dynamin 2-enriched dorsal membrane ruffling and subsequent macropinocytosis in myoblast. The membrane flaccidity-induced local phosphatidic acid production depends on phospholipase D2 (PLD2) that is activated via lipid raft disruption. Furthermore, the \"membrane flaccidity-PLD2-macropinocytosis\" pathway is dominant in myotube, reflecting a potential mechanism of membrane tension homeostasis upon intensive muscle stretching and relaxation. Together, we identify a new mechanotransduction pathway which converts acute tension drop into PA production and subsequently initiates macropinocytosis via actin and dynamin activities.\n\nSummaryWe reveal a mechanical induction of macropinocytosis that is elicited by acute decrease of plasma membrane tension, followed by lipid raft destabilization, PLD2 activation and PA production.

cell biology↗