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Lee, Y. K.

Publications and source records attributed to Lee, Y. K..

17 recordsLinked to original sources

Historical plant embryos as alternative sources of ancient DNA for whole genome sequencing

Natural history and agricultural collections, which contain hundreds of millions of specimens classified in terms of time, space, and taxonomy, are valuable resources for diverse fields of research. Since the first success of ancient DNA (aDNA) isolation in the 1980s, these repositories, including herbaria for plants, have been intensively used to support studies in taxonomy, macroevolution, and genetic responses to anthropogenic activities over the past centuries. Two major challenges of aDNA research are environmental contamination and DNA degradation. For herbarium specimens, aDNA is usually extracted from leaf samples. It is highly fragmented (typically length of 50 to 100 bp) with a higher breakdown rate than that in most bone remains. To optimise the amount of data retrieved and minimise destructive sampling, we isolated DNA from an unconventional plant tissue type - seed embryos. We carried out whole-genome sequencing and compared sequenced DNA quality between embryo and leaf tissue. We evaluated endogenous DNA proportion, median fragment length, damage fraction per site ({lambda}), decay rates, nucleotide misincorporations, and library complexity for three species: cultivated rice Oryza sativa, wild rice O. rufipogon, and wild barley Hordeum spontaneum. In O. sativa, embryos exhibited significantly higher endogenous content and median fragment length than leaves, while in O. rufipogon only median fragment length was higher. The superior DNA preservation was likely due to the protective role of the seed husk, which might play an important role in DNA preservation in plants collected in the tropics. By contrast, in temperate H. spontaneum, tissue type had minimal impact on DNA quality. Despite the minuscule size of the embryos, all derived genomic libraries were highly complex, sufficient for deep whole genome sequencing. These results highlight seed embryos as a promising alternative aDNA source for millions of herbarium specimens, and enable effective genomic analyses of other historical plant collections, such as economic botany and anthropological museum collections.

genomics↗

Genetic architecture of miRNA expression in human brain and its contribution to brain disorders

MicroRNAs (miRNAs) regulate nearly all protein-coding genes and play critical roles in gene regulation, yet the mechanisms governing miRNA regulation remain poorly understood. Here, we examined the genetic architecture of miRNA expression in 995 human brain tissues spanning four regions and two ancestries (African and European) from neurotypical controls and individuals with three psychiatric disorders (schizophrenia, major depressive disorder, and bipolar disorder). We found that miRNA expression is highly dynamic across brain regions, with region-specific differences exceeding those attributable to ancestry or psychiatric diagnosis. Through miRNA expression quantitative trait loci (miR-eQTL) analyses, we identified genetic variants associated with miRNA expression in a region- and ancestry-dependent manner. Overall, miRNAs exhibited heritability levels comparable to protein-coding genes and were positively co-regulated with their host transcripts. Notably, miRNA-regulating genetic variants were enriched in enhancers active in oligodendrocytes and in binding sites of the transcription factor OLIG2, suggesting miRNA-mediated gene regulation in oligodendrocyte lineage. Finally, we identified 15 miRNAs as likely causative factors for psychiatric and neurodegenerative disorders such as major depressive disorder and Alzheimers disease. Together, our results reveal the genetic underpinnings of miRNA regulation in the human brain and suggest that miRNAs serve as key intermediaries linking genetic variation to complex neuropsychiatric and neurological phenotypes.

genomics↗

Spared Nav1.8-Positive Nociceptors Drive Persistent Tactile Hypersensitivity After Sciatic Nerve Crush Injury in Mice

Peripheral nerve injury can lead to chronic mechanical hypersensitivity, yet the severity and persistence of pain are strongly influenced by the extent of axonal damage. Notably, partial sciatic nerve crush injury (PCI) produces persistent tactile hypersensitivity despite a less severe anatomical insult than full crush injury (FCI), yet the identity and post-injury state of the fibers that persist after PCI remain unclear. To define sensory neuron populations contributing to PCI-induced tactile hypersensitivity, we combined fiber-specific transgenic labeling (Thy1-YFP for A{beta} mechanoreceptors and Nav1.8-tdTomato for nociceptors) with pharmacological silencing using QX-314 coapplied with TRPV1 (capsaicin) and TLR5 (flagellin) agonists to selectively manipulate fiber subtypes. At day 7 after PCI, Nav1.8+ nociceptive terminals were still detectable in the hind paw. On day 30, acute silencing of TRPV1+ afferents transiently reduced mechanical hypersensitivity, indicating nociceptor activity in its maintenance. Whole-cell patch-clamp recordings of retrogradely labeled DRG neurons showed that remaining medium-diameter neurons exhibited reduced rheobase and increased action potential firings in response to step current injections. Besides, electrical stimulation of nociceptive fibers increased pERK expression in the spinal dorsal horn, indicating enhanced nociceptive signaling after PCI. Early ablation of TRPV1+ fibers with high-dose capsaicin during degeneration phase prevented the subsequent development of long-term tactile hypersensitivity. Collectively, our results suggest that spared nociceptors after PCI remain sensitized even during nerve repair, driving long-term tactile hypersensitivity. Targeting these spared nociceptive fibers after nerve injury may offer a potential strategy for preventing chronic pain associated with traumatic nerve injury. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/687306v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1331beorg.highwire.dtl.DTLVardef@26e75aorg.highwire.dtl.DTLVardef@1ecf05org.highwire.dtl.DTLVardef@a96e0b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Peripheral Nerve Transection Predominantly Drives Sympathetic Nerve Sprouting in Mouse Dorsal Root Ganglia

Sympathetic sprouting in dorsal root ganglia (DRG) is a feature of sympathetically maintained pain (SMP) following peripheral nerve injury, yet the factors determining its occurrence remain unclear. Here, we compare transection and crush injury models to determine if injury type or site influence sympathetic remodeling and pain. Using TH-IR immunostaining and Phox2b reporter mice to selectively label sympathetic fibers, we found that an L5 spinal nerve transection (SpNT) triggered robust sympathetic fiber sprouting and elevated norepinephrine (NE) levels in the DRG, correlating with a mechanical hypersensitivity reversed by chemical sympathectomy. In contrast, a partial sciatic nerve crush injury (PCI) produced long-lasting mechanical hypersensitivity without sympathetic sprouting or NE elevation and was unaffected by sympathectomy. Importantly, sympathetic sprouting was consistently more pronounced after transection injuries at both spinal and sciatic nerve sites, suggesting that injury type, rather than location, is a dominant factor shaping sympathetic remodeling. These findings establish nerve transection as a key driver of sympathetic sprouting and SMP, whereas crush-induced pain likely involves distinct non-sympathetic mechanisms. This distinction has important implications for pain subtype identification and treatment strategies.

neuroscience↗

Quantitative Membrane Binding Assays Reveal an Inhibitory Role for the BRAF-Specific Region in CRD and Lipid Interaction

BRAF is a serine/threonine kinase and a central effector of the mitogen-activated protein kinase (MAPK) signaling pathway, frequently mutated in cancer. Its activation is tightly controlled by autoinhibitory mechanisms that regulate membrane recruitment and dimerization. The BRAF-specific region (BSR), located at the N-terminus, is known to promote isoform-preferred RAS binding and facilitate dimerization with kinase suppressor of RAS (KSR), yet its role in regulating lipid interaction has remained unexplored. Here, we identify the BSR as a previously unrecognized inhibitory module that attenuates lipid binding by the cysteine-rich domain (CRD). Using quantitative in vitro reconstitution with supported lipid bilayers and fluorescence microscopy, we demonstrate that the BRAF CRD exhibits high intrinsic affinity for phosphatidylserine-rich membranes, but the inclusion of the BSR markedly reduces the membrane binding. We further demonstrate that the inhibitory function of the BSR correlates with its global electrostatic properties rather than a single defined sequence motif. This inhibitory effect of BSR was corroborated in live cells by quantifying plasma membrane localization of BRAF constructs, including the full-length protein. When canonical autoinhibition of CRD--mediated by sequestration within the 14-3-3 dimer--is disrupted by oncogenic mutation or RAF inhibitor treatment, the BSR assumes a compensatory role in repressing CRD-lipid interaction. This additional regulatory layer provided by the BSR prevents RAS-independent membrane recruitment under both physiological and pathological conditions. Broad Impact StatementProtein-lipid interactions are a fundamental mechanism for regulating the localization and activity of signaling proteins. This study reveals that the N-terminal segment of BRAF acts as an inhibitory module that suppresses lipid engagement by CRD, particularly when canonical autoinhibition is disrupted by oncogenic mutation or inhibitor treatment. This additional layer of regulation provides new insight into BRAF membrane dynamics and may have implications in therapeutic intervention of dysregulated BRAF signaling.

biochemistry↗

NKG2D receptor ligands are cell surface biomarkers for injured murine and human nociceptive sensory neurons

Nociceptors are primary afferent neurons that sense noxious stimuli. They can be activated by tissue injury as well as the accompanying local immune response. We have shown that following nerve injury in mice cytotoxic Natural Killer (NK) cells infiltrate the peripheral nerve and interact with stress-induced ligands of the activating receptor NKG2D (Klrk1). However, the diversity and specificity of NKG2D receptor ligands among sensory neuron subtypes, and translation of this mechanism to humans, remains unknown. We used dorsal root ganglion (DRG) neurons cultured from C57BL/6J mice of both sexes with fluorescently-labelled sensory neuron lineages (Scn10a, Mrgprd, Calca, Trpv1, Th, Thy1), as well as human induced pluripotent stem cell derived (hiPSCd)-sensory neurons after laser ablation, as in vitro models of axonal injury. We assessed expression of NKG2D ligands by quantitative polymerase chain reaction (PCR) corroborated by publicly available RNA sequencing datasets and validated with single-cell PCR. Recombinant NKG2D receptor proteins in live cell-based assays were used to reveal the subcellular membrane localisation of NKG2D ligands with quantification by a semi-automated image analysis. Functional interactions between human NK cells and sensory neurons were confirmed with co-cultures in microfluidic devices. We show that NKG2D ligands are expressed exclusively in unmyelinated DRG neurons after injury. NKG2D-receptors bound to puncta along distal neurites of injured axons enriched predominantly in Mrgprd-expressing non-peptidergic nociceptors. We observed low-level binding of human NKG2D-receptors to neurites of hiPSCd sensory neurons that increased after axonal laser ablation. Degeneration of hiPSCd sensory neurons neurites by interleukin (IL-2) primed human NK cells was prevented by an NKG2D blocking antibody. The induction and enrichment of functional NKG2D receptor ligands selectively on pathological nerve fibres could aid the diagnosis of peripheral neuropathy in chronic pain conditions, and sheds new light on the potential role of nociceptive neurons in regulating the local tissue immune microenvironment.

neuroscience↗

Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding

RAF activation requires interactions with both RAS nanoclusters and membrane lipids, yet the molecular basis of this process remains unclear. Using a bottom-up reconstitution approach, we show how coordinated protein-protein and protein-lipid interactions regulate membrane binding dynamics of RAF to drive its multistep activation. Within membrane environments, the RAS-binding domain (RBD) and cysteine-rich domain (CRD) exhibit cooperativity, with CRD-mediated phosphatidylserine binding stabilizing the RBD:RAS complex. Importantly, RAF remains membrane-bound through lateral rebinding to RAS, where a weak CRD-lipid interaction plays an essential role. This lateral rebinding extends RAFs membrane dwell time under high RAS density conditions, which are found in RAS nanoclusters. This prolonged membrane residence likely facilitates kinetic proofreading of RAFs multistep activation within RAS nanoclusters, ensuring signaling specificity. Given the high abundance of weak multivalent membrane interactions, lateral rebinding may be a common mechanism for regulating the activity of signaling proteins through sustained membrane retention.

biochemistry↗

TrkB-dependent regulation of molecular signaling across septal cell types

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimers.

neuroscience↗

Massively Parallel Dissection of RNA in RNA-protein interactions in vivo

Many of the biological functions performed by RNA are mediated by RNA-binding proteins (RBPs), and understanding the molecular basis of these interactions is fundamental to molecular biology. Here, we present MPRNA-immunoprecipitation (MPRNA-IP), an adaptation of the previously developed massively parallel RNA assay (MPRNA), and a new avenue for in vivo high-throughput dissection of RNA-protein interactions. By using custom pools of tens of thousands of RNA sequences containing systematically designed truncations and mutations, we are able to identify RNA domains, sequences, and secondary structures necessary and sufficient for protein binding in a single experiment. We show that this approach is successful for multiple RNAs of interest including NORAD, MS2, and human telomerase RNA, and we describe statistical models for identifying RNA domains and parsing the structural contributions of RNA in these interactions. By blending modern and classical approaches, MPRNA-IP provides a novel high-throughput way to elucidate RNA-based mechanisms behind RNA-protein interactions.

genomics↗

Engineered bacteria detect tumor DNA in vivo

Advances in bacterial engineering have catalysed the development of living cell diagnostics and therapeutics1-3, including microbes that respond to gut inflammation4, intestinal bleeding5, pathogens6 and hypoxic tumors7. Bacteria can access the entire gastrointestinal tract8 to produce outputs measured in stool4 or urine7. Cellular memory, such as bistable switches4,9,10 or genomic rearrangements11, allows bacteria to store information over time. However, living biosensors have not yet been engineered to detect specific DNA sequences or mutations from outside the cell. Here, we engineer naturally competent Acinetobacter baylyi to detect donor DNA from the genomes of colorectal cancer (CRC) cells, organoids and tumors. We characterize the functionality of the biosensors in vitro with co-culture assays and then validate in vivo with sensor bacteria delivered to mice harboring colorectal tumors. We observe horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of CRC. The sensor bacteria achieved 100% discrimination between mice with and without CRC. This Cellular Assay of Targeted, CRISPR-discriminated Horizontal gene transfer (CATCH), establishes a framework for biosensing of mutations or organisms within environments that are difficult to sample, among many other potential applications. Furthermore, the platform could be readily expanded to include production and delivery of antibiotic or antineoplastic therapeutic payloads at the detection site.

synthetic biology↗

Single-cell analysis of human trophoblast stem cell specification reveals activation of fetal cytotrophoblast expression programs including coronavirus associated host factors and human endogenous retroviruses

The human placenta is increasingly a focus of research related to early child development and the impact of maternal hyperimmune states. Primary human trophoblast stem cells (hTSC) and human pluripotent stem cells (hPSC) differentiated to hTSC can potentially model placental processes in vitro. Yet, it remains controversial how the differentiation of human pluripotent stem cells to trophectoderm relates to in vivo development and the factors required for this differentiation. Here, we demonstrate that the primed pluripotent state retains potency to generate trophoblast stem cells by activating EGF and WNT and inhibiting TGFb, HDAC and ROCK signaling without exogenous BMP4 (named TS). We map this specification by temporal single cell RNAseq compared to activating BMP4 or activating BMP4 and inhibiting WNT. TS conditions generate a stable proliferating cell type that is highly similar to six-week placental cytotrophoblasts with activation of endogenous retroviral genes and without amnion expression. Multiple primed iPSC and ES lines differentiate to iPS-derived-TSCs that can be passaged for at least 30 passages and differentiate to pure populations of multinucleated syncytiotrophoblasts and extravillous trophoblast cells. Our findings establish that primed iPS cell specification to hTSC with TS conditions involves induction of TMSB4X, BMP5/7, GATA3 and TFAP2A without transitioning through a naive state. Collectively, our results suggest that the primed state is on a continuum of potency and can differentiate to trophoblast stem cells via multiple paths. Significance StatementIn the present study, we map the specification of primed induced pluripotent stem cells to trophoblast stem cells (TSC). Primed iPS-derived-TSC share transcriptional, morphological and functional characteristics with human ex vivo cytotrophoblasts including capacity of self-renewal and the ability to differentiate to pure extravillous and syncytiotrophoblasts. iPS-derived TSC display a uniquely active transcriptional network of human endogenous retroviruses similar to in vivo trophoblast. In addition, the fast conversion of primed iPSC to TSC allows for modeling placental diseases from large pluripotent stem cell cohorts which are traditionally banked at the primed state. Collectively, our results suggest that the primed state is on a continuum of potency which can differentiate to trophoblast stem cells via multiple paths.

developmental biology↗

Raf promotes dimerization of the Ras G-domain with increased allosteric connections

Ras dimerization is critical for Raf activation, yet Ras alone does not dimerize. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics (MD) simulations show robust allosteric connections linking the two Raf-RBD D113 residues, located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 [A] apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.

biophysics↗

Breakage of the Oligomeric CaMKII Hub by the Regulatory Segment of the Kinase

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a dodecameric or tetradecameric enzyme with crucial roles in neuronal signaling and cardiac function. Activation of CaMKII is reported to trigger the exchange of subunits between holoenzymes, which can increase spread of the active state. Using mass spectrometry, we now show that peptides derived from the sequence of the CaMKII- regulatory segment can bind to the CaMKII- hub assembly and break it into smaller oligomers. Molecular dynamics simulations show that the regulatory segments can dock spontaneously at the interface between hub subunits, trapping large fluctuations in hub structure. Single-molecule fluorescence intensity analysis of human CaMKII- isolated from mammalian cells shows that activation of CaMKII- results in the destabilization of the holoenzyme. Our results show how the release of the regulatory segment by activation and phosphorylation could allow it to destabilize the hub, producing smaller CaMKII assemblies that can reassemble to form new holoenzymes.

bioinformatics↗

Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation

The activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) depends on the balance between activating and inhibitory autophosphorylation (Thr 286 and Thr 305/306, respectively, in the human isoform). Variation in the lengths of the flexible linkers that connect the kinase domains of CaMKII to a central oligomeric hub could alter transphosphorylation rates within a holoenzyme, thereby affecting the balance of autophosphorylation outcomes. Using a single-molecule assay for visualization of CaMKII phosphorylation on glass, we show that the balance of autophosphorylation is flipped between CaMKII- and CaMKII-{beta}, the two principal isoforms in the brain. CaMKII-, with a [~]30 residue kinase-hub linker, readily acquires activating autophosphorylation, which we show is resistant to removal by phosphatases. CaMKII-{beta}, with a [~]200 residue kinase-hub linker, is biased towards inhibitory autophosphorylation. Thus, the responsiveness of CaMKII to calcium signals can be tuned by varying the relative levels of the and {beta} isoforms.

biophysics↗

Fertility of Pedicellate Spikelets in Sorghum is Controlled by a Jasmonic Acid Regulatory Module

As in other cereal crops, the panicles of sorghum (Sorghum bicolor (L.) Moench) comprise two types of floral spikelets (grass flowers). Only sessile spikelets (SSs) are capable of producing viable grains, whereas pedicellate spikelets (PSs) cease development after initiation and eventually abort. Consequently, grain number per panicle (GNP) is lower than the total number of flowers produced per panicle. The mechanism underlying this differential fertility is not well understood. To investigate this issue, we isolated a series of EMS-induced multiseeded (msd) mutants that result in full spikelet fertility, effectively doubling GNP. Previously, we showed that MSD1 is a TCP (Teosinte branched/Cycloidea/PCF) transcription factor that regulates jasmonic acid (JA) biosynthesis, and ultimately floral sex organ development. Here, we show that MSD2 encodes a lipoxygenase (LOX) that catalyzes the first committed step of JA biosynthesis. Further, we demonstrate that MSD1 binds to the promoters of MSD2 and other JA pathway genes. Together, these results show that a JA-induced module regulates sorghum panicle development and spikelet fertility. The findings advance our understanding of inflorescence development and could lead to new strategies for increasing GNP and grain yield in sorghum and other cereal crops.\n\nSignificanceThrough a single base pair mutation, grain number can be increased by ~200% in the globally important crop Sorghum bicolor. This mutation affects the expression of an enzyme, MSD2, that catalyzes the jasmonic acid pathway in developing floral meristems. The global gene expression profile in this enzymatic mutant is similar to that of a transcription factor mutant, msd1, indicating that disturbing any component of this regulatory module disrupts a positive feedback loop that occurs normally due to regular developmental perception of jasmonic acid. Additionally, the MSD1 transcription factor is able to regulate MSD2 in addition to other jasmonic acid pathway genes, suggesting that it is a primary transcriptional regulator of this hormone signaling pathway in floral meristems.

plant biology↗

Development and evaluation of a rapid on-site water pathogen detection system for water quality monitoring

Timely response to outbreak of water-borne diseases caused by bacteria requires efficient monitoring and rapid detection strategies. Herein, we report a rapid DNA-based on-site detection system for specific detection of Pseudomonas aeruginosa. To evaluate the test performance of our method against spiked water samples, parallel tests based on real-time PCR and standard culture methods were concurrently performed. Test sensitivities of between 96.7% and 92.3% were obtained, based on the calculation obtained from qPCR and culture test, respectively, with a corresponding level of specificity of 92.9% and 83.3%. Time-to-result is around 45 min, with a detection limit of 1 CFU/100 mL. Here, a fully-deployable detection method where bacteria of-interest can be detected rapidly with high accuracy was described. This test method can be modified to detect other bacteria of-interest and can also be used in different applications. The test results can be obtained on-site and can therefore be particularly useful in public facilities health surveillance, where regulators can quickly determine if a site is safe or if other emergency response measures are required.\n\nIMPORTANCEPseudomonas aeruginosa is a well-established water quality biomarker, known to be associated to humans health risks. To ascertain the presence of this pathogen, relevant stakeholders currently rely on standard quantitative ISO methods (APHA 9213E) which require 6 days from sampling to results. This window could potentially lead to waterborne outbreaks if the contaminated water features are not shut down for proper and urgent mitigation. This manuscript describes a method to detect this disease-causing microorganism in its viable forms under 1 hour, with a sensitivity of 1 CFU/100mL. Besides providing valuable information of the quality of water system, this direct monitoring of pathogens can reduce substantial time needed from sampling to reporting. This method can be established as a platform technology for other pathogenic microorganisms. On-going work to develop economic point-of-care prototypes could facilitate quick screening of targeted waterborne pathogens and results in better assessment of public health risk and quick in devising emergency response measures and other management strategies.

microbiology↗

Endoplasmic Reticulum Retention Motif Fused to Recombinant Anti-cancer Monoclonal Antibody (mAb) CO17-1A Affects mAb Expression and Plant Stress Response

The endoplasmic reticulum (ER) is the main site of protein synthesis, folding, and secretion to other organelles. The capacity of the ER to process proteins is limited, and excessive accumulation of unfolded and misfolded proteins can induce ER stress, which is associated with plant diseases. Here, a transgenic Arabidopsis system was established to express anti-cancer monoclonal antibodies (mAbs) that recognize the tumor-associated antigen GA733-2. The ER retention Lys-Asp-Glu-Leu (KDEL) motif sequence was added to the C-terminus of the heavy chain to retain anti-colorectal cancer mAbs in the ER, consequently boosting mAb production. Agrobacterium-mediated floral dip transformation was used to generate T1 transformants, and homozygous T4 seeds obtained from transgenic Arabidopsis plants expressing anti-colorectal cancer mAbs were used to confirm the physiological effects of KDEL tagging. Germination rates were not significantly different between mAb CO and mAb COK. However, mAb COK primary root lengths were shorter than those of mAb CO plants and non-transgenic Arabidopsis plants in in vitro media. Most ER stress-related genes, with the exception of bZIP28 and IRE1a, were upregulated in mAb COK plants compared to mAb CO plants. Western blot and SDS-PAGE analyses showed that mAb COK plants exhibited up to five-times higher expression and mAb amounts than mAb CO plants. Enhanced expression in mAb COK plants was confirmed by immunohistochemical analyses. mAb COK was distributed across most of the area of leaf tissues, whereas mAb CO was mainly distributed in extracellular areas. Surface plasmon resonance analyses revealed that both mAb CO and mAb COK possessed equivalent or slightly better binding activities to antigen EpCAM compared to a commercially available parental antibody. These results suggest that the introduction of the KDEL motif is a promising strategy for obtaining enhanced amounts of recombinant therapeutic proteins, but the KDEL sequence may induce ER stress and slightly reduce plant biomass.

plant biology↗