Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 451 records · Page 25Linked to original sources

bioRxiv2026

Neural representation of action grammar structure in primate frontal cortex

Humans and other animals can solve new problems, even on the first attempt. This capacity to generate novel problem-solving behavior has been hypothesized to depend on brain mechanisms for recombining units of knowledge using systems of procedural rules, or grammars. Yet, whether and how the brain represents and implements grammars remains unclear, in large part due to the lack of neural recordings (typically performed in animal models) during grammar-based problem solving (typically studied in humans). Here, we address that gap, and in turn identify an underlying neural basis of grammatical behavior. We designed a visual-motor construction task in which macaque monkeys trace complex, often novel, geometric figures by generating a sequence of strokes, each a distinct shape, like a circle, dash, or chevron (action symbols1). Critically, sequencing was guided by a learned hierarchical action grammar AnBmCk, meaning "repeat shape A, then repeat shape B, then repeat shape C", where the number of repetitions (n, m, and k) varied across problems. Behavior was internally generated (no cues guiding stroke order), problem-directed (to construct a specific image), and exhibited zero-shot generalization (successful on the first trial for novel problems, including harder ones)--key hallmarks of grammar use. To identify underlying neural substrates, we recorded from multiple frontal cortical areas previously implicated in rule use or action sequencing. Activity during drawing encoded key structural properties of the action grammar: (i) shape index (A, B, C), (ii) abstract role (e.g., the role A independent of the specific shape), and (iii) ordinal position within a shape repeat. Moreover, all three properties were strongest in a single region, the pre-supplementary motor area (preSMA). We suggest the possibility that this conjunction of representations is a signature of an implementation of an iterative algorithm resembling a "for-loop" program: internally tracking how many repetitions remain for each shape index and switching to the next when complete. Our study establishes a paradigm for studying the neural basis of grammar-guided novel behavior and identifies in preSMA a dynamic representation of grammatical structure supporting such behavior.

neuroscience↗

bioRxiv2026

The heat-ramp method to study regulated cell death in a pathogenic yeastCryptococcus neoformans

Human fungal pathogens cause a significant public health burden. While no reliable surveilence data are available, estimations suggest that 1 billion infections and over 2 million deaths are attributable to fungal infections annually worldwide. This drove the World Health Organization to generate a priority list of fungal pathogens for reearch, which includes the yeast Cryptococcus neoformans in a top critical priority. With the rise of drug-resistance and emerging fungal pathogens, new conceptual strategies for antifungal therapies are needed in addition to existing antibiotic development pipelines to meet clinical needs. Intrinsic cell death pathways encoded by pathogenic fungi are largely unstudied but could be leveraged for antifungal therapy analogous to anti-cancer therapeutics that activate apoptosis or other cell death mechanisms. Thus far, molecularly defined fungal cell death mechanisms are best characterized for only a few, predominantly model filamentous species. To extend these studies to pathogenic yeast, here we describe and demonstrate a tunable heat-ramp stimulus that when applied to small volumes of yeast cell suspensions reveals a protracted cell death process in the pathogenic yeast Cryptococcus neoformans. This low cost protocol induces robust and reproducible phenotypes to study gene-dependent mechanisms in laboratory strains and clinical isolates.

microbiology↗

bioRxiv2026

Iterative Bump-and-hole engineering creates a bioorthogonal reporter for N-acetylglucosaminyltransferase I

Asparagine-linked protein glycosylation is among the most frequent modifications of proteins trafficking through the secretory pathway. These glycans are manufactured in an assembly line process to a common precursor that is then subject to individual modifications with different levels of complexity. An important biosynthetic modulator is the incorporation of N-acetylglucosamine (GlcNAc) at distinct positions in N-linked glycan biosynthesis, commencing with the activity of the glycosyltransferase MGAT1. While mapping of N-glycans to their corresponding protein attachment sites is generally possible, not much is known about the glycoprotein substrate choice for MGAT1 and related transferases. Analogs of GlcNAc with small bioorthogonal tags can be incorporated into N-glycans. However, due to the promiscuity of some GlcNAc transferases, incorporation is of little specificity towards individual positions. Here, we report an iterative bump-and-hole approach in the design of a bioorthogonal precision tool for the activity of MGAT1 in mammalian cells. Structure-informed protein engineering abrogated the activity of MGAT1 towards the nucleotide-sugar UDP-GlcNAc while retaining activity towards bumped, azide-modified analogs. Kinetic and computational analyses using a neural network approach informed the synthesis of a tailored UDP-GlcNAc analog with preferential acceptance by the engineered enzyme. Following substrate biosynthesis, the strategy allowed selective incorporation of a chemical tag on MGAT1 substrate proteins in living mammalian cells with little background incorporation by other GlcNAc transferases. Our work expands the toolbox for glycan-based reporter compounds.

biochemistry↗

bioRxiv2026

THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons

Microglia play essential roles in maintaining energy homeostasis, and their dysfunction contributes to metabolic disease. Although high-fat diet (HFD) exposure induces microglial activation, the underlying mechanisms remain poorly defined. Here, we identified a previously unrecognized role for THIK-1 channel in mediating glucose sensing of microglia in arcuate nucleus of the hypothalamus (ARH), during HFD-induced obesity. Pharmacological inhibition of THIK-1 channel with tetrapentylammonium (TPA) suppresses feeding and attenuates body-weight gain in diet induced obese mice. Mechanistically, inhibition of agouti-related peptide (AgRP) neurons is indispensable for TPA-induced hypophagia. Moreover, THIK-1 inhibition promotes microglial phagocytosis of perineuronal nets (PNNs), leading to reduced AgRP neuronal activity and feeding suppression. Together, these findings establish THIK-1 as a critical glucose sensor in hypothalamic microglia and uncover a microglia-dependent pathway through which overnutrition modulates AgRP neuronal activity via PNN remodeling to regulate energy balance, highlighting THIK-1 as a potential therapeutic target for treatment of diet-induced obesity.

neuroscience↗

bioRxiv2026

Plasma proteomics reveal heterogeneous subtypes of depression linked to inflammation and aging

The clinical heterogeneity of depression has defied biological classification, limiting personalized treatment. Previous neuroimaging- or symptom-based subtyping of depression failed to clarify the underlying pathoetiology, while plasma proteins which integrates signals from multiple organ systems, offers a promising way to define biologically grounded subtypes. Using plasma proteomics from 2,127 incident depression cases in a cohort of 53000 individuals, we identified three biologically distinct subtypes differing in inflammation, aging, and metabolic profiles. The most prevalent subtype ( inflammation/ageing) was characterized by aging-related inflammation, poorest prognosis with hippocampal atrophy and highest suicide risk, mediated by age-related amygdala atrophy; this subtype had highest anhedonia burden. A distinct inflammation/energy dysregulation group had metabolic pathway enrichment with high inflammation and lifestyle risk factors (smoking) but no ageing trend, predominantly physical/psychomotor symptoms and decreased thalamic volume. In contrast, the inflammation-resilient group had the lowest inflammatory proteomic loading, lowest depression severity, more resilient lifestyle and increased hippocampal volume. These proteomic signatures, detectable years before symptom onset, enable risk stratification and suggest subtype-specific targeted physical and lifestyle interventions.

neuroscience↗

bioRxiv2026

Reconstructing clone-resolved transcriptional programs from bulk tumor sequencing

Tumor clones acquire distinct transcriptional programs as they evolve, but bulk RNA-seq averages over clonal mixtures and obscures the lineage-specific biology that DNA-sequencing reveals. We present PICTographPlus, the first method to infer clone-resolved transcriptional programs by integrating bulk DNA-derived clonal phylogenies and proportions with bulk RNA-seq alone, without single-cell data. Benchmarked against experimentally measured ground truth, scDNA/scRNA co-profiled cells from a wellDR-seq cancer dataset, across 320 pseudo-bulk replicates spanning four tumor purities and four sample counts and evaluated under seven regularization models, PICTographPlus recovers clone-level expression at mean Pearson r [≥] 0.92 and localizes pathway gains and losses to correct evolutionary branches (median F1 0.31-0.40, well above a no-deconvolution baseline). Applied to multi-region NSCLC, pancreatic precursor lesions, and rapid-autopsy PDAC, it localizes metabolic reprogramming, precursor-to-invasive transitions, and organ-adapted metastatic states to specific clonal branches. PICTographPlus turns standard bulk assays into clone-resolved transcriptional maps, enabling retrospective analyses where single-cell profiling is impractical.

genomics↗

bioRxiv2026

The novel variant IBDV induces inflammatory responses via VP3-mediated pyroptosis by directly targeting Caspase-9

The novel variant infectious bursal disease virus (nVarIBDV), which has been widely prevalent since 2017, threatens the poultry industry by inducing severe bursal atrophy and intense inflammatory responses. Understanding the inflammatory mechanism underlying nVarIBDV infection is critical for preventing virus-induced damage. Pyroptosis, an inflammatory type of programmed cell death, may contribute to the inflammation and bursa of Fabricius damage induced by nVarIBDV. Here, we found that the nVarIBDV infection induced severe inflammatory responses both in vivo and in vitro, which were associated with pyroptosis. Further research revealed that the viral protein VP3 drove pyroptosis induced by nVarIBDV infection by indirectly activating the Caspase-3-GSDME pathway, leading to GSDME cleavage. Mechanistically, VP3 directly interacted with and activated Caspase-9, thereby initiating Caspase-9-Caspase-3-GSDME pathway. More importantly, the Serine 33 of VP3 was identified as the key amino acid for interacting with and activating Caspase-9. Mutation of this residue significantly weakened the ability of VP3 to interact with Caspase-9 and activate the Caspase-9-mediated pyroptosis pathway, altered the binding mode of the Caspase-9-VP3 protein complex, and ultimately reduced the ability of VP3 to induce pyroptosis. In conclusion, our results elucidated a novel mechanism by which nVarIBDV infection induced inflammatory responses whereby viral protein VP3 triggered pyroptosis by targeting the Caspase-9-Caspase-3-GSDME pathway. IMPORTANCEnVarIBDV is globally prevalent and poses a significant threat to the poultry industry by causing inflammation and damage to the bursa of Fabricius. This study revealed that nVarIBDV infection induced inflammatory responses and bursa of Fabricius damage, primarily mediated by the viral protein VP3 targeting Caspase-9 to induce pyroptosis. To our knowledge, this is the first report on the interaction between inflammatory responses induced by IBDV infection and pyroptosis. In addition, serine 33 was identified as the critical amino acid required for maintaining the stability of the interaction between VP3 and Caspase-9 and activation of the Caspase-9-Caspase-3-GSDME cascade pyroptosis pathway and further inflammatory responses. Collectively, our findings not only elucidate a novel mechanism by which nVarIBDV induces pyroptosis and further leads to inflammation but also suggest that the identification of this serine site may represent a potential therapeutic target to block nVarIBDV-induced inflammation and bursa of Fabricius damage.

microbiology↗

bioRxiv2026

A Bear-Specific Coding Exon in TMEM41B Is Associated with Cold Adaptation

AbstractBears exhibit an unusual form of hibernation in which core body temperature remains relatively high despite profound suppression of whole-body metabolism. How such a warm yet hypometabolic state is achieved remains poorly understood. Here, through integrative analysis of 238 RNA-seq datasets spanning seven species, we identify transmembrane protein 41B (TMEM41B) as an evolutionarily conserved factor associated with thermogenic capacity. Loss of Tmem41b in mice and Drosophila results in severe cold intolerance, whereas its overexpression enhances thermogenic performance, supporting a conserved role in heat production. Comparative genomic analyses reveal a bear-specific 51-amino acid N-terminal extension in TMEM41B, arising from a 5' untranslated region mutation that converts a premature stop codon into coding sequence. Interactome profiling indicates that this bear-specific isoform differs from the canonical TMEM41B in its protein interaction landscape, including reduced association with components of mitochondria-associated endoplasmic reticulum membranes such as voltage-dependent anion-selective channel protein 1 (VDAC1). Consistent with this altered interaction profile, the extended isoform is associated with reduced mitochondrial oxidative activity. Functional analyses further suggest that the 51- amino acid extension modulates multiple cellular programs, including suppression of oxidative phosphorylation and myogenic differentiation alongside activation of osteogenic pathways, collectively biasing cells toward a hypometabolic state. Notably, expression of the polar bear TMEM41B isoform in mice induces a torpor-like phenotype under fasting conditions. Together, these findings identify TMEM41B as a conserved regulator of thermogenic capacity and suggest that evolutionary modification of its N terminus may contribute to metabolic suppression and energy conservation during bear hibernation.

evolutionary biology↗

bioRxiv2026

Templating and confining calcium phosphate mineralization within designed protein assemblies

Bone formation involves the deposition of ordered hydroxyapatite (HAp) on collagen fibrils, but the underlying molecular mechanisms remain largely unresolved, limiting the design of protein-apatite hybrid materials. Here we show that computationally designed de novo proteins can template and confine HAp mineralization. We design C3-symmetric oligomers with inner surfaces chemically complementary to the HAp {010} facet, and assemble these through additional interfaces into D3 oligomers, one-dimensional nanotubes, and two-dimensional arrays. Electron microscopy revealed templated mineralization and confinement at each hierarchical level, with mineral shape guided by the underlying protein architecture. Conversion of an initially formed amorphous phase to HAp is driven by the designed protein-mineral interface. Our results establish a framework for programmable protein-guided mineralization, providing a foundation for next-generation hybrid materials.

biochemistry↗

bioRxiv2026

ELP1 Gene Augmentation Restores Visual Function in a Mouse Model of Familial Dysautonomia

Familial dysautonomia (FD) is an autosomal recessive sensory and autonomic neurodevelopmental and degenerative disorder characterized by complex neurological phenotypes. One of its most debilitating features is progressive optic neuropathy, which leads to severe visual impairment in FD patients by the third decade of life. Although several preclinical approaches have shown partial rescue of retinal ganglion cell (RGC) degeneration through increasing Elongator acetyltransferase complex subunit 1 (ELP1) expression in the retina, currently no treatments exist to prevent vision loss in FD. In this study, we performed a comprehensive analysis of visual function in a retina-specific FD mouse model (Pax6-Cre;Elp1loxp/loxp) and evaluated a gene supplementation strategy to restore human ELP1 protein levels in the retina. Longitudinal retinal assessments indicated that FD mice exhibit significant retinal nerve fiber layer (RNFL) thinning, as observed in FD patients. FD mice also showed reduced flash visual evoked potentials (VEPs), pattern electroretinography (pERGs), and photopic negative responses (phNRs) amplitudes, along with impaired visual acuity and contrast sensitivity, as assessed using optomotor response assay (OMR). Full-field electroretinography (ffERG) revealed reduced amplitude of dark-adapted a-waves, dark and light-adapted b-waves, indicating combined RGC and bipolar cell dysfunction. Intravitreal delivery of an adeno associated vector (AAV) vector (AAV2.U1a.hELP1) effectively restored physiological ELP1 protein expression, which resulted in a significant rescue of retinal structure and function. Gene supplementation with AAV2.U1a.hELP1 resulted in broad functional and structural improvement compared with untreated FD mice. In summary, our findings provide the first demonstration that ELP1 gene supplementation can effectively rescue RGC function in an FD mouse model and support AAV2.hELP1 at an optimized dose (5.4x108 vg) as a promising therapeutic approach for FD-associated optic neuropathy.

genetics↗

bioRxiv2026

Single-cell characterization of skin response to a bite by West Nile virus-infected mosquito reveals fibroblast-mediated barrier to transmission

Cutaneous events at the mosquito bite site that determine orthoflavivirus transmission efficiency remain largely uncharacterized. Here, we report single-cell RNA-sequencing of skin from immunocompetent mice bitten by West Nile virus-infected mosquitoes, capturing early response at a critical transmission bottleneck. Fibroblasts were the dominant cells exposed to infectious saliva. While neutrophils and Folr2+ macrophages diminished, monocyte-derived and antigen-presenting macrophages, and lymphocytes became more abundant. Cell-cell communication analysis revealed the central roles of fibroblasts and myeloid cells in induced immune-related signaling. Transcriptional profiling defined cell type-specific responses to infectious bite integrating immune modulation, skin repair and metabolic remodeling. Using in vivo gene silencing, we demonstrated that fibroblast-expressed LRRC15 (leucine rich repeat-containing 15) functions as a cutaneous restriction factor, limiting viral replication in skin, viral dissemination to draining lymph nodes, and disease severity. Collectively, our analyses provide cellular and molecular understanding of bite-initiated arboviral transmission, establishing skin-resident fibroblasts as frontline defender cells. HIGHLIGHTSO_LISingle-cell profiling captures early cutaneous response to West Nile virus-infected mosquito bites with cell type resolution. C_LIO_LISkin-resident fibroblasts are the dominant frontline cells exposed to infectious mosquito saliva. C_LIO_LIInfectious bite reconfigures cutaneous immune cells, and activates multi-directional signaling between immune and structural skin cell types. C_LIO_LIBite-induced fibroblast-expressed LRRC15 restricts viral transmission and attenuates disease severity. C_LI

zoology↗

bioRxiv2026

An inducer of snail hibernation causes quiescence and hibernation-like cardioprotection, through metabolic rewiring and autophagy, in mice hearts

Cells of hibernators achieve dormancy, resembling cellular quiescence, through molecular rewiring, metabolic remodelling and autophagy, resisting ischemic and ischemia-reperfusion (IR) injury, while non-hibernators are vulnerable to both. We discovered a circulating dormancy-inducing factor in hibernating snails, synthesized it chemically and because it activates PHLPP1 (a phosphatase regulating the mTOR mediators p-AKT and p-S6K1), named it SNail Activator of PHLPP1 (SNAP). During IR, plasma membrane PHLPP1 and p-AKT translocate to the cytoplasm and mitochondria. SNAP dephosphorylates mitochondrial p-AKT, p-S6K1 and induces dormancy in snails and quiescence (autophagy, reversible cell-cycle exit, proteostasis, apoptosis-resistance) in ischemic mouse fibroblasts. In IR models of cardiomyocytes and perfused hearts, SNAP is cardioprotective by preserving Pyruvate Dehydrogenase (PDH) activity, preventing mitochondrial depolarization, apoptosis and ROS-induced ER stress. SNAPs cardioprotective and mitochondrial effects are absent in hearts with a cardiomyocyte-specific PDH knockout. SNAP reveals fundamental mechanisms of quiescence under stress; while its cardioprotection may be beneficial in the IR injury of normal hearts offered for transplantation, a major challenge in transplant medicine.

cell biology↗

bioRxiv2026

Therapeutic interleukin-2 rewires skeletal-immune circuits to reverse postmenopausal bone loss

Postmenopausal osteoporosis results from excessive osteoclast activity, but the immune circuits that limit osteoclastogenesis in the bone marrow remain poorly understood. Here, we tested a clinically accessible immunotherapy low-dose interleukin-2 (IL-2) as a therapeutic intervention in mice with established ovariectomy-induced bone loss, integrating microcomputed tomography imaging, single-cell transcriptomics, genetic perturbation, and human monocyte-osteoclast assays. Therapeutic administration of IL-2 reversed trabecular bone loss, expanded CXCR3 regulatory T cells in bone marrow, and promoted IL-10- and CGRP-producing ILC2s that were required for protection. IL-2 also acted directly on the osteoclast lineage, suppressing mouse and human osteoclastogenesis through activation of a STAT1-IRF1-dependent IFN program in RANKL-stimulated monocytes. Together, these data define an IL-2-responsive skeletal-immune network that can be therapeutically engaged to suppress osteoclastogenesis, which opens new avenues for cytokine-based immunotherapies in postmenopausal osteoporosis and related bone disorders.

immunology↗

bioRxiv2026

Disrupted dynamics of brain structure function coupling link genetic risk of Alzheimer's Disease and aging to cognitive decline in 34,067 adults

AbstractUnderstanding how a stable structural connectome supports flexible cognition, especially in aging, is a fundamental question in neuroscience. While static structure-function coupling (SFC) is well-studied, the dynamic decoupling of functional activity from structural constraints--dynamic SFC (DSFC)--remains poorly understood. Leveraging MRI data from 34,067 UK Biobank participants (ages 45-82), we characterized the distinct roles of SFC and DSFC in aging, cognition, and health. We found that SFC and DSFC followed spatially divergent aging trajectories: SFC declined primarily in sensorimotor systems, whereas DSFC decreased most prominently in higher-order networks. Both SFC and DSFC in higher-order networks were positively correlated with cognitive performance (e.g., fluid intelligence). However, the associations with mental and physical health diverged between the two measures: reduced DSFC was predominantly linked to health burdens in high-order default/limbic networks, whereas weakened SFC was primarily associated with health burdens in low-order sensory-motor networks. Genetic analyses revealed that Alzheimers risk, specifically APOE {varepsilon}4 dosage, significantly reduced DSFC in higher-order cognitive networks and SFC in visual cortex. Mediation analyses further demonstrated that aging and APOE {varepsilon}4-linked cognitive decline were mediated via visual SFC and ventral attention DSFC. These findings position static and dynamic coupling as complementary mechanisms: static SFC preserves network robustness, while dynamic SFC enables transient reconfiguration for complex integration. Together, our results highlight these dual mechanisms as crucial for maintaining cognitive flexibility, providing potential biomarkers for age-related neurodegeneration.

neuroscience↗

bioRxiv2026

The non-coding facet of Pink1 mRNA regulates mitochondria homeostasis

Coding and non-coding RNAs have traditionally been viewed as functionally distinct entities. Here, we found that the down-regulation of Pink1 due to Tet2 knockout (KO) in muscle cells resulted in mitochondria dysfunction and muscle fatigue. Surprisingly, both Pink1 mRNA alone and untranslatable ATG-deficient Pink1 RNA were sufficient to rescue the mitochondria defects in Tet2 KO cells. PINK1 protein was fast degraded shortly after translation and dispensable for functions of Pink1 mRNA in muscle cells. Moreover, a portion of Pink1 mRNA was located in mitochondria and interacted directly with mitochondria inner membrane located protein YME1L1, promoting its proteolytic cleavage of Opa1, a master regulator of mitochondria fusion, to generate the mature protein form. These findings uncovered a bona fide non-coding role for a canonical mRNA, suggesting that translation independent functions could be present in mRNAs with coding potentials, blurring the conventional dichotomy between coding and non-coding RNAs.

cell biology↗

bioRxiv2026

Periplasmic gatekeeping of phage DNA entry by rSAM enzyme-mediated maturation of an effector with His-X-Ser repeats

In the relentless arms race between bacteria and phages, bacteria have evolved a variety of defense strategies to combat phage infection. However, no bacterial system has been identified that specifically target the phage DNA entry phase. Here, we present a novel bacterial antiphage system, termed HXS, which provides broad-spectrum and robust antiphage activity by interfering with phage DNA entry. The HXS system consists of two radical S-adenosylmethionine (rSAM) enzymes (HxsB and HxsC), a small protein (HxsD), and the effector HxsA with a peptidoglycan-binding domain and five His-Xaa-Ser (HXS) repeats. HxsB/HxsC catalyze rSAM enzyme-dependent maturation of HxsA, including N-terminal processing and a site-specific +8 Da modification, thereby producing a periplasmic effector required for HXS defense. Biochemical evidence supports a model in which the matured effector likely engages incoming DNA electrostatically to arrest entry, establishing an rSAM enzyme-modified protein effector in antiphage defense.

microbiology↗

bioRxiv2026

Mechanistic insights into chromatin modulation by the orphan remodeler ATRX

Alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX) is an ATP-dependent chromatin remodeler that performs diverse functions, including spacing nucleosomes, facilitating the deposition of histone variant H3.3, and preventing replication stress. The mechanism by which ATRX modulates chromatin is unknown. Here, our cryo-EM structure revealed that ATRX recognizes and modulates the nucleosome through its C-terminal regions by embracing and unwrapping [~]18 base-pair nucleosomal DNA near the entry/exit sites in the presence of ADP*BeF3. Strikingly, the DNA minor groove between SHL6 and SHL7 is profoundly deformed by a "pin-like" structure in ATRX, which uniquely intercalates the aromatic side chain of a phenylalanine into the base stackings. Biochemical assays revealed the crucial role of this phenylalanine in sliding the nucleosome without affecting the ATPase activity. Such a "pin-like" structure mimics a "foot-step" on the DNA ladder, which differentiates ATRX from other remodelers. To translocate the DNA on the nucleosome, two more features, including a disordered insertion that contacts the histone surface and a positively charged loop bridging the cross-gyre interactions, serve as essential anchors for the nucleosome modulation by ATRX. Together, we propose a "climbing" model for how ATRX mobilizes the DNA upon ATP hydrolysis.

biochemistry↗

bioRxiv2026

MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy

ATG2A transfers glycerophospholipids from the endoplasmic reticulum (ER) to support expansion of the isolation membrane at ER membrane contact sites. While a role for ATG18/WIPI4 in targeting ATG2A to the IM is well established, how ATG2A is recruited to the ER remains unclear. In this study, we found that MOSPD3, an atypical VAP family protein, acts an adaptor that recruits ATG2A to the ER. MOSPD3 colocalizes with ATG2A and is specifically enriched at ER sites juxtaposed with the IM during autophagosome formation. Recruitment is mediated by direct interactions between the FFNT (two phenylalanines in a neutral tract) motif in the N-terminal region (NT) of ATG2A and the major sperm protein (MSP) domain of MOSPD3. Co-expression of MOSPD3 with ATG2A-NT, but not a MOSPD3-binding-defective mutant ATG2A-NT-T362A, markedly rescued the autophagic defect caused by ATG2A/B double knockout (DKO). MOSPD3 depletion abolishes ATG2A recruitment to the ER and impedes autophagic flux. Together, this study demonstrates that MOSPD3 functions as an ER adaptor for ATG2A in autophagy.

cell biology↗