Biology subjects

Yi, K.

Publications and source records attributed to Yi, K..

At least 19 recordsLinked to original sources

bioRxiv2026

De novo design of flexible protein interactions with GuideFlip

De novo design of protein binders requires a target structure. However, for flexible targets, such as intrinsically disordered proteins, this structure does not exist until the binder has stabilized the interaction. Such targets are therefore difficult for methods that separate structure generation from sequence design. We introduce GuideFlip, which co-designs structure and sequence through guided discrete flow matching: binder residues are assigned progressively while the complex is re-predicted at each step, allowing the evolving interface to affect the design process. GuideFlip reduces the hydrophobic bias of direct AlphaFold optimization and improves in silico success rates over existing approaches. We release a database of binder candidates for 177 human disordered proteins. Experimentally, we obtain de novo binders to the C-terminus of -synuclein and the disordered amino terminus of RBX1 with hit rates of 13.5% and 41.7%, respectively, and we confirm the epitopes of selected binders by NMR and mutagenesis. Applying GuideFlip to flexibility on the binder side, we design a nanobody that binds the agonist-bound {beta}1-adrenergic receptor in the active state, but not the receptor in its inactive state, with a 75% hit rate and cryo-EM structure confirming the design. GuideFlip enables protein design where bound structures emerge only upon binding.

biophysics↗

bioRxiv2026

p62 protein pleomorphism confers tissue-specific function

Protein structure dictate function, and proteins often perform the same function in different cell/tissue-type environments. Here, we report that in Drosophila melanogaster, the broadly expressed protein p62/SQSTM1 instead performs mutually exclusive functions across tissues - autophagy in midgut and mitochondria-associated proteostasis in muscle. These functional differences arise from tissue-specific secondary and tertiary structures adopted by the same p62 polypeptide, rather than protein abundance, isoforms, post-translational modification, or binding-partner availability. The tissue-specific structures are cell autonomous and resistant to environmental perturbation. Deletion of a short intrinsically disordered region converts muscle p62 to a midgut-like structural and functional state, but this forced switch causes muscle dysfunction, linking tissue-specific physiology to alternative structural states of the same polypeptide. We posit that Drosophila p62 exemplifies a mechanism for tissue-specificity in which intrinsic structural plasticity and the physiochemical/molecular environment of a tissue enable a broadly expressed protein to adopt tissue-specific structure and function.

cell biology↗

bioRxiv2025

Agropyron cristatum genome provides a new insight for wheat improvement with wild relatives

Exploring novel genetic variation for target traits is crucial for advancing wheat breeding and genetic improvement. Since 1990, we have been transferring genes from Agropyron cristatum, a promising wild relative genetic resource featuring robust spike morphology and stress tolerance, into common wheat by distant hybridization. To efficiently harness A. cristatum genes, we de novo assembled a 25.62-Gb high-quality genome of an autotetraploid accession Z559 with 28 chromosomes, and uncovered its specific genome features and an extensive repertoire of genes associated with yield and resistance to abiotic and biotic stresses. We systematically characterized A. cristatum genome introgressions by resequencing 431 wheat-A. cristatum derivatives and cloned the gene AcGNS1, which functions in the regulation of grain number per spike in wheat. Subsequently, we developed an optimized genome-selection model for wheat-A. cristatum breeding derivatives, enabling the rapid selection of new potential varieties. These findings demonstrate a genomic breeding strategy for leveraging novel genetic resources of wild relatives and advancing wheat improvement.

genomics↗

bioRxiv2024

APOBEC3A, not APOBEC3B, drives deaminase mutagenesis in human gastric epithelium

Cancer genomes frequently carry APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-associated DNA mutations, suggesting APOBEC enzymes as innate mutagens during cancer initiation and evolution. However, the pure mutagenic impacts of the specific enzymes among this family that are responsible for APOBEC-associated mutagenesis remain unclear in human normal cell lineage, particularly the comparative mutagenic activities of APOBEC3A and APOBEC3B. Here, we investigated the mutagenic contributions of these enzymes through whole-genome sequencing of human normal gastric organoid lines carrying doxycycline-inducible APOBEC3A or APOBEC3B cassettes. Our findings demonstrated that transcriptional APOBEC3A upregulation led to the acquisition of a massive number of genomic mutations in a few cell cycles. By contrast, APOBEC3B upregulation did not generate a substantial number of mutations in gastric epithelium. APOBEC3B-associated mutagenesis remained insignificant even after a combined inactivation of TP53. Based on the spectrum of acquired mutations after APOBEC3A upregulation, we further analyzed APOBEC3A-associated mutational signatures, encompassing indels mainly composed of 1bp deletions, characteristics of clustered mutations, and selective pressures operative on cells carrying the mutations. Our observations provide a clear foundation for understanding the mutational impact of APOBEC enzymes in human cells.

genomics↗

bioRxiv2024

AIVE: accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the Receptor Binding Motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in Variants of Concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 was detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

genomics↗

bioRxiv2024

Cell extrusion - a novel mechanism driving neural crest cell delamination

Neural crest cells (NCC) comprise a heterogeneous population of cells with variable potency, that contribute to nearly every tissue and organ system throughout the body. Considered unique to vertebrates, NCC are transiently generated within the dorsolateral region of the neural plate or neural tube, during neurulation. Their delamination and migration are crucial events in embryo development as the differentiation of NCC is heavily influenced by their final resting locations. Previous work in avian and aquatic species has shown that NCC delaminate via an epithelial-mesenchymal transition (EMT), which transforms these stem and progenitor cells from static polarized epithelial cells into migratory mesenchymal cells with fluid front and back polarity. However, the cellular and molecular drivers facilitating NCC delamination in mammals are poorly understood. We performed live timelapse imaging of NCC delamination in mouse embryos and discovered a group of cells that exit the neuroepithelium as isolated round cells, which then halt for a short period prior to acquiring the mesenchymal migratory morphology classically associated with most delaminating NCC. High magnification imaging and protein localization analyses of the cytoskeleton, together with measurements of pressure and tension of delaminating NCC and neighboring neuroepithelial cells, revealed these round NCC are extruded from the neuroepithelium prior to completion of EMT. Furthermore, we demonstrate that cranial NCC are extruded through activation of the mechanosensitive ion channel, PIEZO1, a key regulator of the live cell extrusion pathway, revealing a new role for PIEZO1 in neural crest cell development. Our results elucidating the cellular and molecular dynamics orchestrating NCC delamination support a model in which high pressure and tension in the neuroepithelium results in activation of the live cell extrusion pathway and delamination of a subpopulation of NCC in parallel with EMT. This model has broad implications for our understanding of cell delamination in development and disease.

developmental biology↗

bioRxiv2023

Whole-genome sequences reveal zygotic composition in chimeric twins

The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified on mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin families to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine.

genomics↗

bioRxiv2023

Protein Engineering with Lightweight Graph Denoising Neural Networks

Protein engineering faces challenges in finding optimal mutants from the massive pool of candidate mutants. In this study, we introduce a deep learning-based data-efficient fitness prediction tool to steer protein engineering. Our methodology establishes a lightweight graph neural network scheme for protein structures, which efficiently analyzes the microenvironment of amino acids in wild-type proteins and reconstructs the distribution of the amino acid sequences that are more likely to pass natural selection. This distribution serves as a general guidance for scoring proteins toward arbitrary properties on any order of mutations. Our proposed solution undergoes extensive wet-lab experimental validation spanning diverse physicochemical properties of various proteins, including fluorescence intensity, antigen-antibody affinity, thermostability, and DNA cleavage activity. More than 40% of PO_SCPLOWROTC_SCPLOWLGN-designed single-site mutants outperform their wild-type counterparts across all studied proteins and targeted properties. More importantly, our model can bypass the negative epistatic effect to combine single mutation sites and form deep mutants with up to 7 mutation sites in a single round, whose physicochemical properties are significantly improved. This observation provides compelling evidence of the structure-based models potential to guide deep mutations in protein engineering. Overall, our approach emerges as a versatile tool for protein engineering, benefiting both the computational and bioengineering communities.

bioengineering↗

bioRxiv2023

Conditional Protein Denoising Diffusion Generates Programmable Endonucleases

Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This emergence leads to the creation of highly efficient and specialized proteins with wide-ranging applications in scientific, technological, and biomedical domains. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to deliver diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structure and highly conserved amino acids (AAs). Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for a specific protein family. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) Kurthia massiliensis Ago (KmAgo) and Pyrococcus furiosus Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 AAs from their WT templates. Experimental tests demonstrated that the majority of generated proteins show unambiguous activity in DNA cleavage for both KmAgo and PfAgo, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusions remarkable success rate to generate novel sequences for proteins of complex structures and functions in a single step with enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without any supervision from labeled data.

bioengineering↗

bioRxiv2023

Sugar assimilation underlying dietary evolution of Neotropical bats

Specializations in animal diets drive selective demands on morphology, anatomy, and physiology. Studying adaptations linked to diet evolution benefits from examining Neotropical bats, a remarkable group with high taxonomic and trophic diversity. In this study, we performed glucose tolerance tests on wild-caught bats, which revealed distinct responses to three sugars present in different foods: trehalose (insects), sucrose, and glucose (fruits and nectar). Insect-eating bats metabolism responded most strongly to trehalose, while bats with nectar and fruit-based diets exhibited a heightened response to glucose and sucrose, reaching blood glucose levels over 600 and 750 mg/dL. To search for signatures of positive selection in sugar assimilation genes we performed genome analysis of 22 focal bat species and 2 outgroup species. We identified selection in the ancestral vespertilionid branch (insect-eaters) for the digestive enzyme trehalase, while sucrase-isomaltase exhibited selection in branches leading to omnivorous and nectar diets. Unexpectedly, the insect-eating lineage Myotis exhibited sucrase-isomaltase selection, potentially explaining their heightened sucrose assimilation. Furthermore, the genes encoding for glucose transporters, Slc2a3 and Slc2a2, showed selection in nectar and blood feeding bats, with analyses of predicted protein structures supporting modified activity. By examining cellular features of the small intestine, we discovered that dietary sugar proportion strongly impacted numerous digestive traits, providing valuable insight into the physiological implications of the identified molecular adaptations. To elucidate this further, we used HCR RNA-FISH to perform single molecule ex vivo gene expression analysis of enterocyte response to a glucose meal in three focal species. We observed unusually high activity in the glucose transporter Slc2a2 during the fasted state of nectar bats that did not change upon feeding. Comparatively, nectar bats exhibited an enhanced capacity for intestinal absorption of dietary sugar primarily through Slc2a2, while fruit bats relied on increasing levels of Slc5a1. Overall, this study highlights the intricate interplay between molecular, morphological, and physiological aspects of diet evolution and provides new insights into our understanding of dietary diversification and sugar assimilation mechanisms in mammals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/547432v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@744e5dorg.highwire.dtl.DTLVardef@1c4e6fcorg.highwire.dtl.DTLVardef@18baaforg.highwire.dtl.DTLVardef@18853ee_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISugar assimilation differences emphasize metabolic adaptations to diet C_LIO_LIGlucose tolerance tests provide a quick and practical assessment of dietary ecology C_LIO_LIBat genomes exhibit positive selection on digestive enzymes and glucose transporters C_LIO_LIStructural comparisons of proteins suggest altered activity of glucose transporters C_LIO_LIGlucose absorption differences can be explained by gut anatomy C_LIO_LIIntestinal villus diversity and novel microanatomy in bats C_LIO_LIExtreme blood glucose (above 600 and 750 mg/dL) coincides with constitutive expression of apical Slc2a2 C_LIO_LIThe regulation of apical Slc2a2 highlights differences in blood glucose levels C_LI

evolutionary biology↗

bioRxiv2022

AIM1-dependent high basal SA accumulation modulates stomatal aperture in rice

The basal levels of salicylic acid (SA), an important plant hormone, vary dramatically among plant species. In the shoot, for example, the monocot plant rice contains almost 100 times higher SA levels than the dicot model plant Arabidopsis. Despite its high basal levels, neither the biosynthetic pathway nor the biological functions of SA is well understood in rice. Here, we report that the synthesis of basal SA in rice shoot is not altered in the mutant for the ISOCHORISMATE SYNTHASE (ICS) gene, but drastically reduced in the mutant for OsAIM1, which encodes a beta-oxidation enzyme in the phenylalanine ammonia-lyase (PAL) pathway. Analogous to its role in thermogenesis, compromised SA accumulation in the Osaim1 mutant led to a lower shoot temperature than wild-type plants. However, this shoot temperature defect was resulted from increased transpiration due to elevated steady-state stomatal aperture in the mutant. Furthermore, the high basal shoot SA level is required for sustained expression of WRKY45 to modulate the steady-state stomatal aperture and shoot temperature in rice. Taken together, these results provide the direct genetic evidence for the critical role of the PAL pathway in the biosynthesis of high levels of basal SA, which play an important role in the regulation of steady-state stomatal aperture to promote fitness under both normal and stress conditions.

plant biology↗

bioRxiv2022

Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility

Physical inactivity - specifically the lack of moderate-to-vigorous activity - is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing unique evolutionary insight into adaptive physical inactivity. The Mexican cavefish Astyanax mexicanus lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3-fold slower than their river-dwelling counterpart. We found that this was accompanied by a marked shift in body composition, decreasing muscle mass by 30% and increasing fat mass by 40%. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated this shift in investment is driven by increased expression of ppar{gamma} - the master regulator of adipogenesis - with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming velocity. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omics analysis indicated metabolic reprogramming, specifically increased phosphoglucomutase-1 abundance, phosphorylation, and activity, as contributing mechanisms enhancing cavefish glycogen utilization under metabolically strenuous conditions. Collectively, we reveal broad skeletal muscle reprogramming following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction under fatiguing conditions. SignificanceThe evolutionary consequence of decreased physical activity upon skeletal muscle physiology remains unexplored. Using the Mexican cavefish, we find loss of moderate-to-vigorous swimming following cave colonization has resulted in broad shifts in skeletal muscle investment - away from muscle mass and instead toward fat and sugar accumulation - ultimately decreasing muscle fiber twitch kinetics. Surprisingly though, cavefish possessed marked muscular endurance, reaching maximal swimming speeds rivaling their river-dwelling counterpart. Multi-omics analysis revealed carbohydrate metabolic reprogramming as a contributing component, most notably elevated abundance and phosphorylation of the glycogenolytic enzyme Phosphoglucomutase-1 - a likely adaptation to cave-specific hypoxia. These findings emphasize the impact multiple selective pressures have on skeletal muscle physiology, providing the first evolutionary insight into skeletal muscle adaptation following decreased activity.

evolutionary biology↗

bioRxiv2021

Impact of cilia-related genes on mitochondrial dynamics during Drosophila spermatogenesis

Spermatogenesis is a dynamic process of cellular differentiation that generates the mature spermatozoa required for reproduction. Errors that arise during this process can lead to sterility due to low sperm counts and malformed or immotile sperm. While is estimated that 1 out of 7 couples encounter infertility, the underlying cause of male infertility can only be identified in 50% of cases. Here, we describe and examine the genetic requirements for missing minor mitochondria (mmm), sterile affecting ciliogenesis (sac), and testes of unusual size (tous), three previously uncharacterized genes that are predicted to be components of the flagellar axoneme. Using Drosophila, we demonstrate that these genes are essential for male fertility and that loss of mmm, sac, or tous results in complete immotility of the sperm flagellum. Cytological examination uncovered additional roles for sac and tous during cytokinesis and transmission electron microscopy of developing spermatids in mmm, sac, and tous mutant animals revealed defects associated with mitochondria and the accessory microtubules required for the proper elongation of the mitochondria and flagella during ciliogenesis. This study highlights the complex interactions of cilia-related proteins within the cell body and advances our understanding of male infertility by uncovering novel mitochondrial defects during spermatogenesis.

developmental biology↗

bioRxiv2021

Mutational impact and signature of ionizing radiation

Whole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated [~]16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In [~]30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.

genomics↗

bioRxiv2020

Clonal dynamics in early human embryogenesis inferred from somatic mutation

The trillions of cells that constitute the human body are developed from a fertilized egg through embryogenesis. However, cellular dynamics and developmental outcomes of embryonic cells in humans remain to be largely unknown due to the technical and ethical challenges. Here, we explored whole-genomes of 334 single-cell expanded clones and targeted deep-sequences of 379 bulk tissues obtained from various anatomical locations from seven individuals. Using the discovered 1,688,652 somatic mutations as an intrinsic barcode, we reconstructed cellular phylogenetic trees that provide novel insights into early human embryogenesis. Our findings suggest (1) endogenous mutational rate that is higher in the first cell division of life but decreases to ~1 per cell per cell division later in life, (2) universal unequal contribution of early cells into embryo proper resulting from early cellular bottlenecks that stochastically separate epiblasts from embryonic cells (3) uneven differential outcomes of early cells into three germ layers, left-right and cranio-caudal tissues, (4) emergence of a few ancestral cells that will contribute to the substantial fraction of adult blood cells, and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach additionally provides insights into the age-related mutational processes including UV-mediated mutagenesis and loss of chromosome X or Y in normal somatic cells. Taken together, this study scrutinized somatic mosaicism, clonal architecture, and cellular dynamics in human embryogenesis at an unprecedented level and provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.

genomics↗

bioRxiv2020

Single-cell Transcriptome of Bronchoalveolar Lavage Fluid Reveals Dynamic Change of Macrophages During SARS-CoV-2 Infection in Ferrets

Although the profile of immune cells changes during the natural course of SARS-CoV-2 inflection in human patients, few studies have used a longitudinal approach to reveal their dynamic features. Here, we performed single-cell RNA sequencing of bronchoalveolar lavage fluid cells longitudinally obtained from SARS-CoV-2-infected ferrets. Landscape analysis of the lung immune microenvironment showed dynamic changes in cell proportions and characteristics in uninfected control, at 2 days post-infection (dpi) (early stage of SARS-CoV-2 infection with peak viral titer), and 5 dpi (resolution phase). NK cells and CD8+ T cells exhibited activated subclusters with interferon-stimulated features, which were peaked at 2 dpi. Intriguingly, macrophages were classified into 10 distinct subpopulations, and their relative proportions changed over the time. We observed prominent transcriptome changes among monocyte-derived infiltrating macrophages and differentiated M1/M2 macrophages, especially at 2 dpi. Moreover, trajectory analysis revealed gene expression changes from monocyte-derived infiltrating macrophages toward M1 or M2 macrophages and identified the distinct macrophage subpopulation that had rapidly undergone SARS-CoV-2-mediated activation of inflammatory responses. Finally, we found that different spectrums of M1 or M2 macrophages showed distinct patterns of gene modules downregulated by immune-modulatory drugs. Overall, these results elucidate fundamental aspects of the immune response dynamics provoked by SARS-CoV-2 infection.

immunology↗

bioRxiv2020

The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The similar Wtf4antidote protein also forms aggregates but is sequestered within or near vacuoles and is mostly benign. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate sequestration, as mutations that disrupt either of these processes results in cell death. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy gametes.

cell biology↗

bioRxiv2019

Wampa is a dynein subunit required for axonemal assembly and male fertility in Drosophila

Axonemal dyneins are motor proteins that form the inner and outer arms of the axoneme in cilia and flagella. Defects in dynein arms are the leading cause of primary ciliary dyskinesia (PCD), which is characterized by chronic respiratory infections, situs inversus, and sterility. Despite current understanding of pathological features associated with PCD, many of their causative genes still remain elusive. Here we analyze genetic requirements for wampa (wam), a previously uncharacterized component of the outer dynein arm that is essential for male fertility. In addition to a role in outer dynein arm formation, we uncovered additional requirements during spermatogenesis, including regulation of remodeling events for the mitochondria and the nucleus. Due to the conserved nature of axonemal dyneins and their essential role in both PCD and fertility, this study advances our understanding of the pathology of PCD, as well as the functional role of dyneins in axonemal formation and spermatogenesis.

developmental biology↗