Biology subjects

Cote, M.

Publications and source records attributed to Cote, M..

At least 19 recordsLinked to original sources

bioRxiv2024

Nanoparticles co-delivering siRNA and mRNA for simultaneous restoration and silencing of gene/protein expression in vitro and invivo

RNA-based agents such as siRNA, miRNA, and mRNA can selectively manipulate gene expression/proteins and have the potential to revolutionize the current therapeutic strategies for various diseases, including cancer. To address the poor stability and inherent limitations of RNA agents, nanoparticle (NP) platforms have been developed to deliver functional mRNA or siRNA inside the cells. Recent studies have focused on either siRNA to knock down proteins causing drug resistance or mRNA technology to introduce tumor suppressors. However, complex diseases like cancer need multi-targeted approaches to selectively target multiple gene expressions/proteins. In this proof-of-concept study, we developed co-delivery nanoparticles containing Luc-mRNA and siRNA-GFP as model RNA agents ((M+S)-NPs) and assessed their effects in vitro and in vivo. Our studies show that NPs can effectively deliver both functional mRNA and siRNA together, simultaneously impacting the expression of two genes/proteins in vitro. Additionally, after in vivo administration, co-delivery NPs successfully knocked down GFP while introducing luciferase in a TNBC mouse model, indicating our NPs have the potential to develop RNA-based anticancer therapeutics. These studies pave the way to develop RNA-based, multitargeted, multi-delivery approaches for complex diseases like cancer. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/600196v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1668ae2org.highwire.dtl.DTLVardef@1283491org.highwire.dtl.DTLVardef@9336daorg.highwire.dtl.DTLVardef@f654c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses

The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses. AUTHOR SUMMARYThere is a large collection of sarbecoviruses related to SARS-CoV-2 circulating in animal reservoirs with the potential to spillover into humans. Neutralizing antibodies have the potential to protect against infection, although viral escape is common. In this study, we isolated several monoclonal antibodies that show broad activity against different sarbecoviruses. The antibodies target epitopes in the core of the receptor binding domain that are highly conserved in sequence across sarbecoviruses and emerging SARS-CoV-2 variants. One antibody showed remarkable breadth against both SARS-CoV-1 variants as well as diverse sarbecoviruses. The results of deep mutational scanning suggest that mutations at these predicted sites of escape may functionally constrain viral fitness. Our functional profiling of cross-reactive antibodies highlights vulnerable sites of sarbecoviruses, with some antibodies poised as broadly neutralizing candidates for therapeutic use against future sarbecovirus emergence.

immunology↗

bioRxiv2024

Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

The continued evolution of SARS-CoV-2 requires persistent monitoring of its subvariants. Omicron subvariants are responsible for the vast majority of SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% of circulating strains as of January 2024. In this study, we characterized the functional properties of Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3 BA.2.86 and JN.1. We tested their capacity to evade plasma-mediated recognition and neutralization, ACE2 binding, their susceptibility to cold inactivation, Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared to the early wild-type (D614G) strain, most Omicron subvariants Spike glycoproteins evolved to escape recognition and neutralization by plasma from individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had the best affinity for ACE2 at all temperatures tested. We found that Omicron subvariants Spike processing is associated with their susceptibility to cold inactivation. Intriguingly, we found that Spike-ACE2 binding at low temperature was significantly associated with growth rates of Omicron subvariants in humans. Overall, we report that Spikes from newly emerged Omicron subvariants are relatively more stable and resistant to plasma-mediated neutralization, present improved affinity for ACE2 which is associated, particularly at low temperatures, with their growth rates.

microbiology↗

bioRxiv2023

An Integrated Optogenetic and Bioelectronic Platform for Regulating Cardiomyocyte Function

We report an integrated optogenetic and bioelectronic platform for stable and long-term modulation and monitoring of cardiomyocyte function in vitro. Optogenetic inputs were achieved through expression of a photoactivatable adenylyl cyclase (bPAC), that when activated by blue light caused a dose-dependent and time-limited increase in autonomous cardiomyocyte beat rate. Bioelectronic readouts were achieved through an integrated planar multi-electrode array (MEA) that provided real-time readouts of electrophysiological activity from 32 spatially-distinct locations. Irradiation at 27 W/mm2 resulted in a ca. 14% increase in beat rate within 20-25 minutes, which remained stable for at least 2 hours. The beating rate could be cycled through repeated "on" and "off" states, and its magnitude was a monotonic function of irradiation intensity. Our integrated platform opens new avenues in bioelectronic medicine, including closedloop feedback systems, with potential applications for cardiac regulation including arrhythmia diagnosis and intervention. TeaserA system that integrates optogenetic stimulation and bioelectronic recording capabilities allows for on-demand regulation of cardiac cell function.

bioengineering↗

bioRxiv2023

Interaction Between the Prefrontal and Visual Cortices Supports Subjective Fear

It has been reported that threatening and non-threatening visual stimuli can be distinguished based on the multi-voxel patterns of hemodynamic activity in the human ventral visual stream. Do these findings mean that there may be evolutionarily hardwired mechanisms within early perception, for the fast and automatic detection of threat, and maybe even for the generation of the subjective experience of fear? In this human neuroimaging study, we presented participants (Fear group: N=30; No Fear group: N = 30) with 2700 images of animals that could trigger subjective fear or not as a function of individuals idiosyncratic "fear profiles" (i.e., fear ratings of animals reported by a given participant). We provide evidence that the ventral visual stream may represent affectively neutral visual features that are statistically associated with fear ratings of participants, without representing the subjective experience of fear itself. More specifically, we show that patterns of hemodynamic activity predictive of a specific "fear profile" can be observed in the ventral visual stream whether a participant reports being afraid of the stimuli or not. Further, we found that the multivariate information synchronization between ventral visual areas and prefrontal regions distinguished participants who reported being subjectively afraid of the stimuli from those who did not. Together, these findings support the view that the subjective experience of fear may depend on the relevant visual information triggering implicit metacognitive mechanisms in the prefrontal cortex.

neuroscience↗

bioRxiv2023

The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer

High-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency. Furthermore, we explore the relationship between local ancestry and histologic subtype. We identify one region (chr9q32) wherein the African/European local ancestry diplotype was associated with a higher incidence of serous carcinoma. We also underline a difference in somatic mutation frequency between endometrioid and serous carcinoma. While highly exploratory, these findings begin to characterize the complex relationship between genetic ancestry and characteristics of high-grade endometrial cancer, which may impact patient survival.

genomics↗

bioRxiv2023

Interaction of SCoV-2 NSP7 or NSP8 alone may cause constriction of the RNA entry channel in NSP12: Implications for novel RdRp inhibitor drug discovery

RNA-dependent RNA polymerase (RdRP) is a critical component of the RNA virus life cycle, including SCoV-2. Among the Coronavirus-encoded proteins, non-structural protein 12 (NSP12) exhibits polymerase activity in collaboration with one unit of NSP7 and two units of NSP8, constituting the RdRp holoenzyme. While there is abundant information on SCoV-2 RdRp-mediated RNA replication, the influence of interplay among NSP12, NSP7, and NSP8 on template RNA binding and primer extension activity remains relatively unexplored and poorly understood. Here, we recreated a functional RdRp holoenzyme in vitro using recombinant SCoV-2 NSP12, NSP7, and NSP8, and established its functional activity. Subsequently, molecular interactions among the NSPs in the presence of a variety of templates and their effects on polymerase activity were studied, wherein we found that NSP12 alone exhibited notable polymerase activity that increased significantly in the presence of NSP7 and NSP8. However, this activity was completely shut down, and the template RNA-primer complex was detached from NSP12 when one of the two cofactors was present. Through computational analysis, we found that the template RNA entry channel was more constricted in the presence of one of the two cofactors, which was relatively more constricted in the presence of NSP8 compared to that in the presence of NSP7. In conclusion, we report that NSP7 and NSP8 together synergise to enhance the activity of NSP12, but antagonise when present alone. Our findings have implications for novel drug development, and compounds that obstruct the binding of NSP7 or NSP8 to NSP12 can have lethal effects on viral RNA replication.

molecular biology↗

bioRxiv2022

Sphingosine kinases promote Ebola virus infection and can be targeted to inhibit filoviruses, coronaviruses, and arenaviruses using late endocytic trafficking to enter cells

Entry of enveloped viruses in host cells requires the fusion of the viral and host cell membranes, a process that is facilitated by viral fusion proteins protruding from the viral envelope. For fusion, viral fusion proteins need to be triggered by host factors and for some viruses, such as Ebola virus (EBOV) and Lassa fever virus, this event occurs inside endosomes and/or lysosomes. Consequently, these late-penetrating viruses must be internalized and delivered to entry-conducive intracellular vesicles. Because endocytosis and vesicular trafficking are tightly regulated cellular processes, late penetrating viruses also depend on specific host factors, such as signaling molecules, for efficient viral delivery to the site of fusion, suggesting that these could be targeted for antiviral therapy. In this study, we investigated a role for sphingosine kinases (SKs) in viral entry and found that chemical inhibition of sphingosine kinase 1 (SK1) and/or SK2 and knockdown of SK1 or SK2, inhibited entry of EBOV into host cells. Mechanistically, inhibition of SK1 and/or SK2 prevented EBOV from reaching late-endosomes and lysosomes that are positive for the EBOV receptor, Niemann Pick C1 (NPC1). Furthermore, we present evidence that suggests the trafficking defect caused by SK1/2 inhibition occurs independently of S1P signaling through cell-surface S1PRs. Lastly, we found that chemical inhibition of SKs prevents entry of other late-penetrating viruses, including arenaviruses and coronaviruses, in addition to inhibiting infection by replication competent EBOV and SARS-CoV-2 in Huh7.5 cells. In sum, our results highlight an important role played by SKs in endocytic trafficking which can be targeted to inhibit entry of late-penetrating viruses. SK inhibitors could serve as a starting point for the development of broad-spectrum antiviral therapeutics.

microbiology↗

bioRxiv2022

Molecular basis for antiviral activity of pediatric neutralizing antibodies targeting SARS-CoV-2 Spike receptor binding domain

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV- 2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC-evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

microbiology↗

bioRxiv2022

Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission

Wildlife reservoirs of SARS-CoV-2 may enable viral adaptation and spillback from animals to humans. In North America, there is evidence of unsustained spillover of SARS-CoV-2 from humans to white-tailed deer (Odocoileus virginianus), but no evidence of transmission from deer to humans. Through a biosurveillance program in Ontario, Canada we identified a new and highly divergent lineage of SARS-CoV-2 in white-tailed deer. This lineage is the most divergent SARS-CoV-2 lineage identified to date, with 76 consensus mutations (including 37 previously associated with non-human animal hosts) and signatures of considerable evolution and transmission within wildlife. Phylogenetic analysis also revealed an epidemiologically linked human case. Together, our findings represent the first clear evidence of sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.

microbiology↗

bioRxiv2022

Identification of a SARS-CoV-2 host metalloproteinase-dependent entry pathway differentially used by SARS-CoV-2 and variants of concern Alpha, Delta, and Omicron

To infect cells, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) via its spike glycoprotein (S), delivering its genome upon S-mediated membrane fusion. SARS-CoV-2 uses two distinct entry pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In investigating serine protease-independent cell-cell fusion, we found that the matrix metalloproteinases (MMPs), MMP2/9, can activate SARS-CoV-2 S fusion activity, but not that of SARS-CoV-1. Importantly, metalloproteinase activation of SARS-CoV-2 S represents a third entry pathway in cells expressing high MMP levels. This route of entry required cleavage at the S1/S2 junction in viral producer cells and differential processing of variants of concern S dictated its usage. In addition, metalloproteinase inhibitors reduced replicative Alpha infection and abrogated syncytia formation. Finally, we found that the Omicron S exhibit reduced metalloproteinase-dependent fusion and viral entry. Taken together, we identified a MMP2/9-dependent mode of activation of SARS-CoV-2 S. As MMP2/9 are released during inflammation and severe COVID-19, they may play important roles in SARS-CoV-2 S-mediated cytopathic effects, tropism, and disease outcome.

microbiology↗

bioRxiv2022

VE607 Stabilizes SARS-CoV-2 Spike In the "RBD-up" Conformation and Inhibits Viral Entry

SARS-CoV-2 infection of host cells starts by binding of the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. Here, we present the commercially available VE607, comprised of three stereoisomers, that was originally described as an inhibitor of SARS-CoV-1. We show that VE607 specifically inhibits infection of SARS-CoV-1 and SARS-CoV-2 S-expressing pseudoviral particles as well as authentic SARS-CoV-2. VE607 stabilizes the receptor binding domain (RBD) in its "up" conformation. In silico docking and mutational analysis map the VE607 binding site at the RBD-ACE2 interface. The IC50 values are in the low micromolar range for pseudoparticles derived from SARS-CoV-2 Wuhan/D614G as well as from variants of concern (Alpha, Beta, Gamma, Delta and Omicron), suggesting that VE607 has potential for the development of drugs against SARS-CoV-2 infections.

microbiology↗

bioRxiv2021

SARS-CoV-2 Omicron Spike recognition by plasma from individuals receiving BNT162b2 mRNA vaccination with a 16-weeks interval between doses

Continuous emergence of SARS-CoV-2 variants of concern (VOC) is fueling the COVID-19 pandemic. Omicron (B.1.1.529), is rapidly spreading worldwide. The large number of mutations in its Spike raised concerns about a major antigenic drift that could significantly decrease vaccine efficacy and infection-induced immunity. A long interval between BNT162b2 mRNA doses was shown to elicit antibodies that efficiently recognize Spikes from different VOCs. Here we evaluated the recognition of Omicron Spike by plasma from a cohort of SARS-CoV-2 naive and previously-infected individuals that received their BNT162b2 mRNA vaccine 16-weeks apart. Omicron Spike was recognized less efficiently than D614G, Alpha, Beta, Gamma and Delta Spikes. We compared to plasma activity from participants receiving a short (4-weeks) interval regimen. Plasma from individuals of the long interval cohort recognized and neutralized better the Omicron Spike compared to those that received a short interval. Whether this difference confers any clinical benefit against Omicron remains unknown.

microbiology↗

bioRxiv2021

Contribution of single mutations to selected SARS-CoV-2 emerging variants Spike antigenicity

Towards the end of 2020, multiple variants of concern (VOCs) and variants of interest (VOIs) have arisen from the original SARS-CoV-2 Wuhan-Hu-1 strain. Mutations in the Spike protein are highly scrutinized for their impact on transmissibility, pathogenesis and vaccine efficacy. Here, we contribute to the growing body of literature on emerging variants by evaluating the impact of single mutations on the overall antigenicity of selected variants and their binding to the ACE2 receptor. We observe a differential contribution of single mutants to the global variants phenotype related to ACE2 interaction and antigenicity. Using biolayer interferometry, we observe that enhanced ACE2 interaction is mostly modulated by a decrease in off-rate. Finally, we made the interesting observation that the Spikes from tested emerging variants bind better to ACE2 at 37{degrees}C compared to the D614G variant. Whether improved ACE2 binding at higher temperature facilitates emerging variants transmission remain to be demonstrated.

microbiology↗

bioRxiv2021

Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among {beta}-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

microbiology↗

bioRxiv2020

Consistent and High-Frequency Identification of an Intra-Sample Genetic Variant of SARS-CoV-2 with Elevated Fusogenic Properties

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that is continuously evolving. Although its RNA-dependent RNA polymerase exhibits some exonuclease proofreading activity, viral sequence diversity can be produced by replication errors and host factors. A diversity of genetic variants can be observed in the intra-host viral population structure of infected individuals. Most mutations will follow a neutral molecular evolution and wont make significant contributions to variations within and between infected hosts. Herein, we profiled the intra-sample genetic diversity of SARS-CoV-2 variants using high-throughput sequencing datasets from 15,289 infected individuals and infected cell lines. Most of the genetic variations observed, including C->U and G->U, were consistent with errors due to heat-induced DNA damage during sample processing and/or sequencing protocols. Despite high mutational background, we identified recurrent intra-variable positions in the samples analyzed, including several positions at the end of the gene encoding the viral Spike (S) protein. Strikingly, we observed a high-frequency C->A missense mutations resulting in the S protein lacking the last 20 amino acids (S{Delta}20). We found that this truncated S protein undergoes increased processing and increased syncytia formation, presumably due to escaping M protein retention in intracellular compartments. Our findings suggest the emergence of a high-frequency viral sublineage that is not horizontally transmitted but potentially involved in intra-host disease cytopathic effects. IMPORTANCEThe mutation rate and evolution of RNA viruses correlate with viral adaptation. While most mutations do not have significant contributions to viral molecular evolution, some are naturally selected and cause a genetic drift through positive selection. Many recent SARS-CoV-2 variants have been recently described and show phenotypic selection towards more infectious viruses. Our study describes another type of variant that does not contribute to inter-host heterogeneity but rather phenotypic selection toward variants that might have increased cytopathic effects. We identified that a C-terminal truncation of the Spike protein removes an important ER-retention signal, which consequently results in a Spike variant that easily travels through the Golgi toward the plasma membrane in a pre-activated conformation, leading to increased syncytia formation.

bioinformatics↗

bioRxiv2020

Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

cancer biology↗

bioRxiv2020

Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

The dysregulation of macrophage lipid metabolism drives atherosclerosis. AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics and plays essential roles regulating macrophage lipid dynamics. Here, we investigated the consequences of atherogenic lipoprotein-induced foam cell formation on downstream immunometabolic signaling in primary mouse macrophages. A variety of atherogenic low-density lipoproteins (acetylated, oxidized and aggregated forms) activated AMPK signaling in a manner that was in part, due to CD36 and calcium-related signaling. In quiescent macrophages, basal AMPK signaling was crucial for maintaining markers of lysosomal homeostasis, as well as levels of key components in the lysosomal expression and regulation network. Moreover, AMPK activation resulted in targeted up-regulation of members of this network via transcription factor EB. However, in lipid-induced macrophage foam cells, neither basal AMPK signaling nor its activation affected lysosomal-associated programs. These results suggest that while the sum of AMPK signaling in cultured macrophages may be anti-atherogenic, atherosclerotic input dampens the regulatory capacity of AMPK signaling.

cell biology↗