Biology subjects

Li, B.

Publications and source records attributed to Li, B..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

Dynorphin modulates motivation through a pallido-amygdala cholinergic circuit

The endogenous opioid peptide dynorphin and its receptor {kappa}-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and motivational drive in mice. On one hand, dynorphin acts postsynaptically via KORs on local GABAergic neurons in the VP to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to invigorate reward-seeking behaviors. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine, and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulate motivation through cholinergic system, and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.

neuroscience↗

bioRxiv2024

Reconstitution of chromatin reorganization during mammalian oocyte development

SignificanceThe generation of developmentally competent eggs requires oocyte growth and maturation. When compared to meiotic maturation, relatively little is known about the key processes that happen in growing oocytes. Since the first visualization of oocyte chromatin under the electron microscope, we have known that growing oocytes undergo a fundamental transition from the non-surrounded nucleolus (NSN) to surrounded nucleolus (SN) chromatin configuration. NSN-to-SN transition is crucial for subsequent embryonic development after fertilization, but what drives NSN-to-SN transition during mammalian oocyte development is still unknown. Here we show that natural degradation of RNA polymerase II (RNAPII) by segregase and proteasome drives NSN-to-SN transition, challenging the conventional view that transcriptional silencing and NSN-to-SN transition are driven by independent epigenetic mechanisms in mammalian oocytes. The final step of oocyte growth, which reorganizes chromatin from the uncondensed, non-surrounded nucleolus (NSN) configuration to the condensed, surrounded nucleolus (SN) configuration, is essential for embryonic development after fertilization. However, the mechanism of NSN-to-SN transition remains unknown. Here, we identify RNA polymerase II (RNAPII) degradation as the key driver of this process. RNAPII inhibitors, but not nucleoside-based transcription inhibitors, swiftly induced RNAPII degradation and NSN-to-SN transition in oocytes. Strikingly, induced SN-like nuclei recapitulated epigenetic features, chromatin interactions and developmental potential in SN oocytes. Using segregase and proteasome inhibitors and the newly established scFv miniTrim-Away for nuclear proteins, we further demonstrate that RNAPII degradation is necessary and sufficient for NSN-to-SN transition in mouse and human. RNAPII degradation globally cleared RNAPII from transcriptionally active chromatin and increased chromatin dynamics, concomitantly leading to transcriptional silencing and chromatin rearrangement in oocytes. Our study elucidates the framework of chromatin reorganization in growing mammalian oocytes and provides an alternative source of fully grown oocyte nuclei, representing a milestone for the potential use of growing oocytes in reproductive medicine.

developmental biology↗

bioRxiv2024

Expectation modulates learning emotional words: Evidence from a hierarchical Bayesian model

In language acquisition, individuals learn the emotional value of words through external feedback. Previous studies have used emotional words as experimental materials to explore the cognitive mechanism underlying emotional language processing, but have failed to recognize that languages are acquired in a changing environment. To this end, this study aims to combine reinforcement learning with emotional word learning, using a probabilistic reversal learning task to explore how individuals acquire the valence of emotional words in a dynamically changing environment. Our computational modeling on both behavioral and event-related potential (ERP) data revealed that individuals expectations can modulate the learning speed and temporal processing of emotional words, demonstrating a clear negative bias. Specifically, as the expected value increases, individuals respond faster and exhibit higher amplitudes for negative emotional words. These findings shed light on the neural mechanisms of emotional word learning in a volatile environment, highlighting the crucial role of expectations in this process and the preference for processing negative information.

neuroscience↗

bioRxiv2024

White matter tract crossing and bottleneck regions in the fetal brain

There is a growing interest in using diffusion MRI to study the white matter tracts and structural connectivity of the fetal brain. Recent progress in data acquisition and processing suggests that this imaging modality has a unique role in elucidating the normal and abnormal patterns of neurodevelopment in utero. However, there have been no efforts to quantify the prevalence of crossing tracts and bottleneck regions, important issues that have been extensively researched for adult brains. In this work, we determined the brain regions with crossing tracts and bottlenecks between 23 and 36 gestational weeks. We performed probabilistic tractography on 59 fetal brain scans and extracted a set of 51 distinct white tracts, which we grouped into 10 major tract bundle groups. We analyzed the results to determine the patterns of tract crossings and bottlenecks. Our results showed that 20-25% of the white matter voxels included two or three crossing tracts. Bottlenecks were more prevalent. Between 75-80% of the voxels were characterized as bottlenecks, with more than 40% of the voxels involving four or more tracts. The results of this study highlight the challenge of fetal brain tractography and structural connectivity assessment and call for innovative image acquisition and analysis methods to mitigate these problems.

neuroscience↗

bioRxiv2024

Quantifiable Blood TCR Repertoire Components Associated with Immune Aging

T cell senescence results in decayed adaptive immune protection in older individuals, with decreased or increased abundance of certain T cell phenotypic subpopulations. However, no study has linked aging to the dynamic changes of T cell clones. Through a newly develop computational framework, Repertoire Functional Units (RFU), we investigated over 6,500 TCR repertoire sequencing samples from multiple human cohorts. Our analysis identified age-associated RFUs repeatedly and consistently across different cohorts. Quantification of RFU decreases with aging revealed accelerated loss under immunosuppressive conditions. Systematic analysis of age-associated RFUs in clinical samples manifested a potential link between these RFUs and improved clinical outcomes during acute viral infections, such as lower ICU admission and reduced risk of developing complications. Finally, our investigation of bone-marrow transplantation patients indicated a secondary expansion of the age-associated clones upon receiving stem cells from younger donors. Together, our results suggest the existence of certain clones or a TCR clock that could reflect the immune functions in aging populations.

immunology↗

bioRxiv2024

Bioenergetic stress potentiates antimicrobial resistance and persistence

Antimicrobial resistance (AMR) is a global health crisis and there is an urgent need to better understand AMR mechanisms. Antibiotic treatment alters several aspects of bacterial physiology, including increased ATP utilization, carbon metabolism, and reactive oxygen species (ROS) formation. However, how the "bioenergetic stress" induced by increased ATP utilization affects treatment outcomes is unknown. Here we utilized a synthetic biology approach to study the direct effects of bioenergetic stress on antibiotic efficacy. We engineered a genetic system that constitutively hydrolyzes ATP or NADH in Escherichia coli. We found that bioenergetic stress potentiates AMR evolution via enhanced ROS production, mutagenic break repair, and transcription-coupled repair. We also find that bioenergetic stress potentiates antimicrobial persistence via potentiated stringent response activation. We propose a unifying model that antibiotic-induced antimicrobial resistance and persistence is caused by antibiotic-induced. This has important implications for preventing or curbing the spread of AMR infections.

microbiology↗

bioRxiv2024

Cloud-Connected Patch-Worn Auscultation Device for Chest Sound Monitoring

In recent years, wearable electrocardiograms have risen in popularity as a solution for personal monitoring of heart activity. However, this technology has limitations in diagnostic capability and structural function monitoring. Meanwhile, auscultation of the heart remains a fundamental tool for physicians in diagnosis and monitoring of heart disease largely unaddressed in a convenient wearable format. The present work outlines a promising system currently under investigation, allowing user-initiated 10-second chest-sound recordings to be transmitted over Bluetooth-Low-Energy, with an innovative package design providing inherent noise reduction and a high signal-to-noise ratio. The device has been tested on healthy individuals, and system response has been validated against calibrated electrocardiogram recording equipment to analyze signal capture fidelity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/601965v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@3605fdorg.highwire.dtl.DTLVardef@c362b3org.highwire.dtl.DTLVardef@184e799org.highwire.dtl.DTLVardef@811384_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBP pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/601733v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@7cba6dorg.highwire.dtl.DTLVardef@b37fb2org.highwire.dtl.DTLVardef@84aa8forg.highwire.dtl.DTLVardef@1d9bda2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIUnlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages. C_LIO_LIUnsaturated fatty acids activate the FABP4/CEBP axis for neutral lipid biosynthesis in macrophages C_LIO_LIDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophages C_LIO_LIFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis C_LI

immunology↗

bioRxiv2024

Microsporidian Nosema bombycis secretes serine protease inhibitor to suppress host cell apoptosis via caspase BmICE

Microsporidia are a group of intracellular pathogens that actively manipulate host cell biological processes to facilitate their intracellular niche. Apoptosis is an important defense mechanism by which host cell control intracellular pathogens. Microsporidia modulating host cell apoptosis has been reported previously, however the molecular mechanism is not yet clear. In this report, we describe that the microsporidia Nosema bombycis inhibits apoptosis of Bombyx mori cells through a secreted protein NbSPN14, which is a serine protease inhibitor (Serpin). An immunofluorescent assay demonstrated that upon infection with N. bombycis, NbSPN14 was initially found in the B. mori cell cytoplasm and then became enriched in the host cell nucleus. Overexpression and RNA-interference (RNAi) of NbSPN14 in B. mori embryo cells confirmed that NbSPN14 inhibited host cell apoptosis. Immunofluorescent and Co-IP assays verified the co-localization and interaction of NbSPN14 with the BmICE, the caspase 3 homolog in B. mori. Knocking out of BmICE or mutating the BmICE-interacting P1 site of NbSPN14, eliminated the localization of NbSPN14 into the host nucleus and prevented the apoptosis-inhibiting effect of NbSPN14, which also proved that the interaction between BmICE and NbSPN14 occurred in host cytoplasm and the NbSPN14 translocation into host cell nucleus is dependent on BmICE. These data elucidate that N. bombycis secretory protein NbSPN14 inhibits host cell apoptosis by directly inhibiting the caspase protease BmICE, which provides an important insight for understanding pathogen-host interactions and a potential therapeutic target for N. bombycis proliferation. Author SummaryMicrosporidia constitute a class of eukaryotic pathogens that exclusively reside within host cells. The species Nosema bombycis is the first microsporidian identified as the pathogen of silkworm Pebrine disease. In our research, we discovered how N. bombycis cleverly evades the hosts defenses. It has developed a strategy to survive inside host cells by manipulating host cell apoptosis, disarming the host cells self-destruct mechanism. In this study, we discovered that the N. bombycis secretes a serine protease inhibitor named NbSPN14, which infiltrates the cytoplasm of the host cell. The NbSPN14 interacts with the executioner Caspase protease BmICE within the silkworms apoptotic pathway, effectively neutralizing its apoptoic activity and thus curbing the apoptosis of the host cells.

microbiology↗

bioRxiv2024

Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-{kappa}B activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1{beta} in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1{beta} in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1{beta}, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1{beta}. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1{beta} gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1{beta} signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1{beta} in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1{beta}, will be critical to effectively tailor medication regimens.

neuroscience↗

bioRxiv2024

Application of machine learning in a rodent malaria model for rapid, accurate, and consistent parasite counts

Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually counting parasite-infected red blood cells (iRBCs), a time-consuming process, which can be inconsistent between individuals and labs. We have developed an easy-to-use machine learning (ML)-based software, Malaria Screener R, to expedite and standardize such studies by automating the counting of Plasmodium iRBCs in rodents. This software can process Giemsa-stained blood smear images captured by any camera-equipped microscope. It features an intuitive graphical user interface that facilitates image processing and visualization of the results. The software has been developed as a desktop application that processes images on standard Windows and Mac OS computers. A previous ML model created by the authors designed to count P. falciparum-infected human RBCs did not perform well counting Plasmodium-infected mouse RBCs. We leveraged that model by loading the pre-trained weights and training the algorithm with newly collected data to target P. yoelii and P. berghei mouse iRBCs. This new model reliably measured both P. yoelii and P. berghei parasitemia (R2 = 0.9916). Additional rounds of training data to incorporate variances due to length of Giemsa staining, microscopes etc, have produced a generalizable model, meeting WHO Competency Level 1 for the sub-category of parasite counting using independent microscopes. Reliable, automated analyses of blood-stage parasitemia will facilitate rapid and consistent evaluation of novel vaccines and antimalarials across labs in an easily accessible in vivo malaria model.

microbiology↗

bioRxiv2024

Piximi - An Images to Discovery web tool for bioimages and beyond

Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

cell biology↗

bioRxiv2024

Effects of lysine and methionine on mRNA expression of candidate transcription factors by primary bovine mammary epithelial cells

It has been established that essential amino acids (EAA) regulate protein synthesis in mammary epithelial cells by rapidly altering the phosphorylation state of translation factors. However, the long-term transcriptional response to EAA supply has been investigated much less. Eight transcription factors were selected as candidate mediators of EAA effects on mammary cell function via the amino acid response (ATF4, ATF6), mitogen-activated protein kinase (JUN, FOS, EGR1), and mechanistic target of rapamycin complex 1 (MYC, HIF1A, SREBF1). The objective was to determine if and when expression of these candidate genes was affected in primary cultures of bovine mammary epithelial cells more than 24 h after imposing an EAA deficiency, and to evaluate effects of EAA deficiency on protein synthesis, endoplasmic reticulum size, cell proliferation, and lipogenesis. Differentiated cells were cultured in 1 of 3 treatment media representing normal physiological concentrations of all amino acids (CTL), low lysine (LK), or low methionine (LM) for 24, 40, 48, or 60 h. Both LK and LM suppressed protein synthesis and activated ATF4 expression, indicating the classic amino acid response pathway had been triggered. However, there was no effect of LK or LM on endoplasmic reticulum size, possibly related to elevated ATF6 expression on LM. Expression of early response genes JUN, FOS, EGR1 and MYC was not elevated by EAA deficiency but LM decreased EGR1 expression. LM also increased expression of HIF1A. The EGR1 and HIF1A expression results are consistent with the decrease in cell proliferation rate observed. Variable responses in SREBF1 expression to LK and LM at different timepoints may have contributed to a lack of effect on lipogenesis rates. These findings indicate that EAA deficiency may inhibit mammary protein synthesis and cell proliferation through transcription factors.

cell biology↗

bioRxiv2024

AAV Capsid Screening for Translational Pig Research Using a Mouse Xenograft Liver Model

In gene therapy, delivery vectors are a key component for successful gene delivery and safety, based on which adeno-associated viruses (AAVs) gained popularity in particular for the liver, but also for other organs. Traditionally, rodents have been used as animal models to develop and optimize treatments, but species and organ specific tropism of AAV desire large animal models more closely related to humans for preclinical in-depth studies. Relevant AAV variants with the potential for clinical translation in liver gene therapy were previously evolved in vivo in a xenogeneic mouse model transplanted with human hepatocytes. Here, we selected and evaluated efficient AAV capsids using chimeric mice with a >90% xenografted pig hepatocytes. The pig is a valuable preclinical model for therapy studies due to its anatomic and immunological similarities to humans. Using a DNA-barcoded recombinant AAV library containing 47 different capsids and subsequent Illumina sequencing of barcodes in the AAV vector genome DNA and transcripts in the porcine hepatocytes, we found the AAVLK03 and AAVrh20 capsid to be the most efficient delivery vectors regarding transgene expression in porcine hepatocytes. In attempting to validate these findings with primary porcine hepatocytes, we observed capsid-specific differences in cell entry and transgene expression efficiency where the AAV2, AAVAnc80, and AAVDJ capsids showed superior efficiency to AAVLK03 and AAVrh20. This work highlights intricacies of in vitro testing with primary hepatocytes and the requirements for suitable pre-clinical animal models but suggests the chimeric mouse to be a valuable model to predict AAV capsids to transduce porcine hepatocytes efficiently.

molecular biology↗

bioRxiv2024

Amd1-skp2 cascade regulates hepatocyte proliferation during liver growth and hepatocellular carcinoma development in zebrafish

Rapid hepatocyte proliferation is a common characteristic of liver growth in early liver development and hepatocellular carcinoma (HCC). Clarifying the mechanism how liver growth is regulated in development would benefit studying HCC progress. Although many genes have been reported to be involved in liver growth during early development, the mechanism underlying liver growth is far from being elucidated. Here we found that the liver undergoes rapid growth from 2dpf to 5dpf in zebrafish. Comparing the transcriptome for different staged hepatocytes identified 813 hepatocyte enriched genes at 3 dpf. Among them, S-adenosylmethionine decarboxylase proenzyme (AMD1) had not been previously reported to be involved in liver development. Our study further confirmed that amd1 was highly enriched in hepatocytes during liver rapid growth and that amd1 mutation inhibited liver growth mainly by repressing hepatocyte proliferation. Mechanistically, amd1 loss of function downregulated the expression of skp2, and skp2 is required for amd1 to regulate hepatocyte proliferation. Furthermore, the role of Amd1-Skp2 cascade in regulating hepatocyte proliferation was also conserved in a zebrafish HCC model. In conclusion, our study systematically identified some uncharacterized genes possibly being involved in regulating liver growth during zebrafish development, and revealed the role of amd1-skp2 cascade in regulating hepatocyte proliferation during liver growth and HCC progression. This work also provided a database which would benefit elucidating the mechanism how hepatocyte proliferation is regulated during liver growth and HCC progress.

developmental biology↗

bioRxiv2024

Mesendodermal cells fail to contribute to heart formation following blastocyst injection

Blastocyst complementation offers an opportunity for generating transplantable whole organs from donor sources. Pluripotent stem cells (PSCs) have traditionally served as the primary donor cells due to their ability to differentiate into any type of body cell. However, the use of PSCs raises ethical concerns, particularly regarding their uncontrollable differentiation potential to undesired cell lineages such as brain and germline cells. To address this issue, various strategies have been explored, including the use of genetically modified PSCs with restricted lineage potential or lineage-specified progenitor cells as donors. In this study, we tested whether nascent mesendodermal cells (MECs), which appear during early gastrulation, can be used as donor cells. To do this, we induced Bry-GFP+ MECs from mouse embryonic stem cells (ESCs) and introduced them into the blastocyst. While donor ESCs gave rise to various regions of embryos, including the heart, Bry-GFP+ MECs failed to contribute to the host embryos. This finding suggests that MECs, despite being specified from PSCs within a few days, lack the capacity to assimilate into the developing embryo.

developmental biology↗

bioRxiv2024

Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-Tumor Immunity by Activating cGAS/STING Signaling

Hepatocellular carcinoma (HCC) is a highly lethal cancer for which current available treatment options have limited efficacy. Immunotherapy has emerged as a promising therapeutic option for HCC, yet resistance to immunotherapy is a major challenge. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a novel driver of immunotherapy resistance in HCC. We show that PRMT3 expression is induced by activated T cells in response to immune checkpoint blockade (ICB) via an interferon-gamma (IFN{gamma})-STAT1 signaling pathway, and that high PRMT3 expression inversely correlates with tumor-infiltrating CD8+ T cells and predicts poor response to ICB in HCC patients. We demonstrate that genetic depletion and pharmacological inhibition of PRMT3 induce a profound influx of T cells into tumors and activate anti-tumor immunity to suppress HCC progression. Mechanistically, we demonstrate that PRMT3 methylates HSP60, a mitochondrial chaperone protein, at R446, and that this novel post-translational modification is required for HSP60 oligomerization and maintaining mitochondrial homeostasis. We reveal that targeting PRMT3-dependent HSP60-R446 methylation boosts anti-tumor immunity by disrupting mitochondrial function, increasing mitochondrial DNA (mtDNA) leakage, and activating the cGAS/STING pathway, a key innate immune sensor of cytosolic DNA. Importantly, we provide genetic and pharmacologic evidence that targeting PRMT3 enhances anti-PD1 efficacy and anti-tumor immunity in HCC mouse models. Our study identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

cancer biology↗

bioRxiv2024

PRR adjuvants restrain high stability peptides presentation on APCs

Adjuvants can affect APCs function and boost adaptive immune responses post-vaccination. However, whether they modulate the specificity of immune responses, particularly immunodominant epitope responses, and the mechanisms of regulating antigen processing and presentation remain poorly defined. Here, using overlapping synthetic peptides, we screened the dominant epitopes of Th1 responses in mice post-vaccination with different adjuvants and found that the adjuvants altered the antigen-specific CD4+ T-cell immunodominant epitope hierarchy. MHC-II immunopeptidomes demonstrated that the peptide repertoires presented by APCs were significantly altered by the adjuvants. Unexpectedly, no novel peptide presentation was detected after adjuvant treatment, whereas peptides with high binding stability for MHC-II presented in the control group were missing after adjuvant stimulation, particularly in the MPLA- and CpG-stimulated groups. The low-stability peptide present in the adjuvant groups effectively elicited robust T-cell responses and formed immune memory. Collectively, our results suggest that adjuvants (MPLA and CpG) inhibit high-stability peptide presentation instead of revealing cryptic epitopes, which may alter the specificity of CD4+ T-cell-dominant epitope responses. The capacity of adjuvants to modify peptide-MHC (pMHC) stability and antigen-specific T-cell immunodominant epitope responses has fundamental implications for the selection of suitable adjuvants in the vaccine design process and epitope vaccine development.

immunology↗