Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

Ehrlichia chaffeensisinvades and survives in phagocytes by modulating host cell processes and evading innate defenses, but the mechanisms are not fully defined. Recently we have determined thatE. chaffeensistandem repeat proteins (TRPs) are type 1 secreted effectors involved in functionally diverse interactions with host targets, including components of the evolutionarily conserved Wnt signaling pathways. In this study, we demonstrated that induction of host canonical and noncanonical Wnt pathways byE. chaffeensisTRP effectors stimulates phagocytosis and promotes intracellular survival. AfterE. chaffeensisinfection, canonical and noncanonical Wnt signalings were significantly stimulated during early stages of infection (1 to 3 h) which coincided with dephosphorylation and nuclear translocation of β-catenin, a major canonical Wnt signal transducer, and NFATC1, a noncanonical Wnt transcription factor. In total, the expression of ∼44% of Wnt signaling target genes was altered during infection. Knockdown of TRP120-interacting Wnt pathway components/regulators and other critical components, such as Wnt5a ligand, Frizzled 5 receptor, β-catenin, nuclear factor of activated T cells (NFAT), and major signaling molecules, resulted in significant reductions in the ehrlichial load. Moreover, small-molecule inhibitors specific for components of canonical and noncanonical (Ca2+and planar cell polarity [PCP]) Wnt pathways, including IWP-2, which blocks Wnt secretion, significantly decreased ehrlichial infection. TRPs directly activated Wnt signaling, as TRP-coated microspheres triggered phagocytosis which was blocked by Wnt pathway inhibitors, demonstrating a key role of TRP activation of Wnt pathways to induce ehrlichial phagocytosis. These novel findings reveal thatE. chaffeensisexploits canonical and noncanonical Wnt pathways through TRP effectors to facilitate host cell entry and promote intracellular survival.

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Ehrlichia chaffeensis TRP32 Interacts with Host Cell Targets That Influence Intracellular Survival

Infection and Immunity ◽

10.1128/iai.00154-12 ◽

2012 ◽

Vol 80 (7) ◽

pp. 2297-2306 ◽

Cited By ~ 33

Author(s):

Tian Luo ◽

Jere W. McBride

Keyword(s):

Host Cell ◽

Defense Mechanisms ◽

Ring Finger ◽

Elongation Factor ◽

Intracellular Survival ◽

Mononuclear Phagocytes ◽

Ehrlichia Chaffeensis ◽

Content Type ◽

Cell Defense

ABSTRACTEhrlichia chaffeensisis an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes and survives by evading host cell defense mechanisms. Recently, molecular interactions ofE. chaffeensistandem repeat proteins 47 and 120 (TRP47 and -120) and the eukaryotic host cell have been described. In this investigation, yeast two-hybrid analysis demonstrated that anE. chaffeensistype 1 secretion system substrate, TRP32, interacts with a diverse group of human proteins associated with major biological processes of the host cell, including protein synthesis, trafficking, degradation, immune signaling, cell signaling, iron metabolism, and apoptosis. Eight target proteins, including translation elongation factor 1 alpha 1 (EF1A1), deleted in azoospermia (DAZ)-associated protein 2 (DAZAP2), ferritin light polypeptide (FTL), CD63, CD14, proteasome subunit beta type 1 (PSMB1), ring finger and CCCH-type domain 1 (RC3H1), and tumor protein p53-inducible protein 11 (TP53I11) interacted with TRP32 as determined by coimmunoprecipitation assays, colocalization with TRP32 in HeLa and THP-1 cells, and/or RNA interference. Interactions between TRP32 and host targets localized to theE. chaffeensismorulae or in the host cell cytoplasm adjacent to morulae. Common or closely related interacting partners ofE. chaffeensisTRP32, TRP47, and TRP120 demonstrate a molecular convergence on common cellular processes and molecular cross talk betweenEhrlichiaTRPs and host targets. These findings further support the role of TRPs as effectors that promote intracellular survival.

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Nuclear Translocated Ehrlichia chaffeensis Ankyrin Protein Interacts with a Specific Adenine-Rich Motif of Host Promoter and Intronic Alu Elements

Infection and Immunity ◽

10.1128/iai.00376-09 ◽

2009 ◽

Vol 77 (10) ◽

pp. 4243-4255 ◽

Cited By ~ 72

Author(s):

Bing Zhu ◽

Kimberly A. Nethery ◽

Jeeba A. Kuriakose ◽

Abdul Wakeel ◽

Xiaofeng Zhang ◽

...

Keyword(s):

Host Cell ◽

Gene Transcription ◽

Target Genes ◽

Nuclear Translocation ◽

Specific Binding ◽

Binding Motif ◽

Ehrlichia Chaffeensis ◽

Whole Genome Analysis ◽

Alu Elements ◽

Cell Gene

ABSTRACT Ehrlichiae are obligately intracellular bacteria that reside and replicate in phagocytes by circumventing host cell defenses and modulating cellular processes, including host cell gene transcription. However, the mechanisms by which ehrlichiae influence host gene transcription have largely remained undetermined. Numerous ankyrin and tandem repeat-containing proteins associated with host-pathogen interactions have been identified in Ehrlichia species, but their roles in pathobiology are unknown. In this study, we determined by confocal immunofluorescence microscopy and by immunodetection in purified nuclear extracts that the ankyrin repeat-containing protein p200 is translocated to the nuclei of Ehrlichia-infected monocytes. Chromatin immunoprecipitation (ChIP) with DNA sequencing revealed an Ehrlichia chaffeensis p200 interaction located within host promoter and intronic Alu-Sx elements, the most abundant repetitive elements in the human genome. A specific adenine-rich (mid-A-stretch) motif within Alu-Sx elements was identified using electrophoretic mobility shift and NoShift assays. Whole-genome analysis with ChIP and DNA microarray analysis (ChIP-chip) determined that genes (n = 456) with promoter Alu elements primarily related to transcription, apoptosis, ATPase activity, and structural proteins associated with the nucleus and membrane-bound organelles were the primary targets of p200. Several p200 target genes (encoding tumor necrosis factor alpha, Stat1, and CD48) associated with ehrlichial pathobiology were strongly upregulated during infection, as determined by quantitative PCR. This is the first study to identify a nuclear translocation of bacterially encoded protein by E. chaffeensis and to identify a specific binding motif and genes that are primary targets of a novel molecular strategy to reprogram host cell gene expression to promote survival of the pathogen.

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Ehrlichia chaffeensis TRP32 Is a Nucleomodulin That Directly Regulates Expression of Host Genes Governing Differentiation and Proliferation

Infection and Immunity ◽

10.1128/iai.00657-16 ◽

2016 ◽

Vol 84 (11) ◽

pp. 3182-3194 ◽

Cited By ~ 12

Author(s):

Tierra R. Farris ◽

Paige S. Dunphy ◽

Bing Zhu ◽

Clayton E. Kibler ◽

Jere W. McBride

Keyword(s):

Dna Binding ◽

Host Cell ◽

Gene Transcription ◽

Noncoding Rna ◽

Target Genes ◽

Immune Cell ◽

Luciferase Reporter ◽

Ehrlichia Chaffeensis ◽

Content Type

Ehrlichia chaffeensis is an obligately intracellular bacterium that reprograms the mononuclear phagocyte through diverse effector-host interactions to modulate numerous host cell processes, including transcription. In a previous study, we reported that E. chaffeensis TRP32, a type 1 secreted effector, interacts with multiple host nucleus-associated proteins and also autoactivates reporter gene expression in yeast. In this study, we demonstrate that TRP32 is a nucleomodulin that binds host DNA and alters host gene transcription. TRP32 enters the host cell nucleus via a noncanonical translocation mechanism that involves phosphorylation of Y179 located in a C-terminal trityrosine motif. Both genistein and mutation of Y179 inhibited TRP32 nuclear entry. An electromobility shift assay (EMSA) demonstrated TRP32 host DNA binding via its tandem repeat domain. TRP32 DNA-binding and motif preference were further confirmed by supershift assays, as well as competition and mutant probe analyses. Using chromatin immunoprecipitation with next-generation sequencing (ChIP-seq), we determined that TRP32 binds a G-rich motif primarily within ±500 bp of the gene transcription start site. An ontology analysis identified genes involved in processes such as immune cell differentiation, chromatin remodeling, and RNA transcription and processing as primary TRP32 targets. TRP32-bound genes ( n = 1,223) were distributed on all chromosomes and included several global regulators of proliferation and inflammation such as those encoding FOS, JUN, AKT3, and NRAS and noncoding RNA genes microRNA 21 (miRNA 21) and miRNA 142. TRP32 target genes were differentially regulated during infection, the majority of which were repressed, and direct repression/activation of these genes by TRP32 was confirmed in vitro with a cellular luciferase reporter assay.

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Ehrlichia chaffeensis TRP120 Is a Wnt Ligand Mimetic That Interacts with Wnt Receptors and Contains a Novel Repetitive Short Linear Motif That Activates Wnt Signaling

mSphere ◽

10.1128/msphere.00216-21 ◽

2021 ◽

Vol 6 (2) ◽

Author(s):

Madison R. Rogan ◽

LaNisha L. Patterson ◽

Caitlan D. Byerly ◽

Tian Luo ◽

Slobodan Paessler ◽

...

Keyword(s):

Wnt Signaling ◽

Wnt Pathway ◽

Immune Cell ◽

Direct Interaction ◽

Enzyme Linked Immunosorbent Assay ◽

Ehrlichia Chaffeensis ◽

Linear Motif ◽

Pathway Activity ◽

Content Type ◽

Canonical Wnt

ABSTRACT Ehrlichia chaffeensis expresses the TRP120 multifunctional effector, which is known to play a role in phagocytic entry, on the surface of infectious dense-cored ehrlichiae, but a cognate host receptor has not been identified. We recently reported that E. chaffeensis activates canonical Wnt signaling in monocytes to promote bacterial uptake and intracellular survival and that TRP120 was involved in this activation event. To identify the specific mechanism of pathway activation, we hypothesized that TRP120 is a Wnt signaling ligand mimetic that initiates Wnt pathway activity through direct interaction with the Wnt pathway Frizzled family of receptors. In this study, we used confocal immunofluorescence microscopy to demonstrate very strong colocalization between E. chaffeensis and Fzd2, 4, 5, 7, and 9 as well as coreceptor LRP5 at 1 to 3 h postinfection. Direct binding between TRP120 and multiple Fzd receptors was further confirmed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). Interfering RNA knockdown of Wnt receptors, coreceptors, and signaling pathway components significantly reduced E. chaffeensis infection, demonstrating that complex and redundant interactions are involved in Wnt pathway exploitation. We utilized in silico approaches to identify a repetitive short linear motif (SLiM) in TRP120 that is homologous to Wnt ligands and used mutant SLiM peptides and an α-TRP120-Wnt-SLiM antibody to demonstrate that the TRP120 Wnt SLiM activates the canonical Wnt pathway and promotes E. chaffeensis infection. This study reports the first example of bacterial mimicry of Wnt pathway ligands and highlights a pathogenic mechanism with potential for targeting by antimicrobial therapeutics. IMPORTANCE Upon infecting mammalian hosts, Ehrlichia chaffeensis establishes a replicative niche in microbe-eating immune system cells where it expertly orchestrates infection and spread. One of the ways Ehrlichia survives within these phagocytes is by activating evolutionarily conserved signaling pathways including the Wnt pathway; however, the molecular details of pathway hijacking have not been defined. This study is significant because it identifies an ehrlichial protein that directly interacts with components of the Wnt receptor complex, influencing pathway activity and promoting infection. Consequentially, Ehrlichia serves as a unique tool to investigate the intricacies of how pathogens repurpose human immune cell signaling and provides an opportunity to better understand many cellular processes in health and disease. Furthermore, understanding how this bacterium utilizes its small genome to survive within cells that evolved to destroy pathogens will facilitate the development of antibacterial therapeutics that could target Ehrlichia as well as other intracellular agents of human disease.

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Biogenesis of the Spacious Coxiella-Containing Vacuole Depends on Host Transcription Factors TFEB and TFE3

Infection and Immunity ◽

10.1128/iai.00534-19 ◽

2019 ◽

Vol 88 (3) ◽

Cited By ~ 2

Author(s):

Bhavna Padmanabhan ◽

Laura F. Fielden ◽

Abderrahman Hachani ◽

Patrice Newton ◽

David R. Thomas ◽

...

Keyword(s):

Transcription Factors ◽

Host Cell ◽

Isotope Labeling ◽

Nuclear Translocation ◽

Bacterial Pathogen ◽

Effector Proteins ◽

Content Type ◽

Cellular Processes ◽

Type Iv ◽

Lysosome Biogenesis

ABSTRACT Coxiella burnetii is an obligate intracellular bacterial pathogen that replicates inside the lysosome-derived Coxiella-containing vacuole (CCV). To establish this unique niche, C. burnetii requires the Dot/Icm type IV secretion system (T4SS) to translocate a cohort of effector proteins into the host cell, which modulate multiple cellular processes. To characterize the host-pathogen interactions that occur during C. burnetii infection, stable-isotope labeling by amino acids in cell culture (SILAC)-based proteomics was used to identify changes in the host proteome during infection of a human-derived macrophage cell line. These data revealed that the abundances of many proteins involved in host cell autophagy and lysosome biogenesis were increased in infected cells. Thus, the role of the host transcription factors TFEB and TFE3, which regulate the expression of a network of genes involved in autophagy and lysosomal biogenesis, were examined in the context of C. burnetii infection. During infection with C. burnetii, both TFEB and TFE3 were activated, as demonstrated by the transport of these proteins from the cytoplasm into the nucleus. The nuclear translocation of these transcription factors was shown to be dependent on the T4SS, as a Dot/Icm mutant showed reduced nuclear translocation of TFEB and TFE3. This was supported by the observation that blocking bacterial translation with chloramphenicol resulted in the movement of TFEB and TFE3 back into the cytoplasm. Silencing of the TFEB and TFE3 genes, alone or in combination, significantly reduced the size of the CCV, which indicates that these host transcription factors facilitate the expansion and maintenance of the organelle that supports C. burnetii intracellular replication.

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EtpE Binding to DNase X Induces Ehrlichial Entry via CD147 and hnRNP-K Recruitment, Followed by Mobilization of N-WASP and Actin

mBio ◽

10.1128/mbio.01541-15 ◽

2015 ◽

Vol 6 (6) ◽

Cited By ~ 12

Author(s):

Dipu Mohan Kumar ◽

Mingqun Lin ◽

Qingming Xiong ◽

Mathew James Webber ◽

Comert Kural ◽

...

Keyword(s):

Cell Surface ◽

Host Cell ◽

Actin Polymerization ◽

Ehrlichia Chaffeensis ◽

Content Type ◽

Hnrnp K ◽

Obligate Intracellular ◽

Human Proteins ◽

Coated Bead ◽

Human Monocytic Ehrlichiosis

ABSTRACTObligate intracellular bacteria, such asEhrlichia chaffeensis, perish unless they can enter eukaryotic cells.E. chaffeensisis the etiological agent of human monocytic ehrlichiosis, an emerging infectious disease. To infect cells,Ehrlichiauses theCterminus of the outer membrane invasinentry-triggeringprotein (EtpE) ofEhrlichia(EtpE-C), which directly binds the mammalian cell surface glycosylphosphatidyl inositol-anchored protein, DNase X. How this binding drivesEhrlichiaentry is unknown. Here, using affinity pulldown of host cell lysates with recombinant EtpE-C (rEtpE-C), we identified two new human proteins that interact with EtpE-C: CD147 and heterogeneous nuclear ribonucleoprotein K (hnRNP-K). The interaction of CD147 with rEtpE-C was validated by far-Western blotting and coimmunoprecipitation of native EtpE with endogenous CD147. CD147 was ubiquitous on the cell surface and also present around foci of rEtpE-C-coated-bead entry. Functional neutralization of surface-exposed CD147 with a specific antibody inhibitedEhrlichiainternalization and infection but not binding. Downregulation of CD147 by short hairpin RNA (shRNA) impairedE. chaffeensisinfection. Functional ablation of cytoplasmic hnRNP-K by a nanoscale intracellular antibody markedly attenuated bacterial entry and infection but not binding. EtpE-C also interacted with neuronal Wiskott-Aldrich syndrome protein (N-WASP), which is activated by hnRNP-K. Wiskostatin, which inhibits N-WASP activation, and cytochalasin D, which inhibits actin polymerization, inhibitedEhrlichiaentry. Upon incubation with host cell lysate, EtpE-C but not an EtpE N-terminal fragment stimulatedin vitroactin polymerization in an N-WASP- and DNase X-dependent manner. Time-lapse video images revealed N-WASP recruitment at EtpE-C-coated bead entry foci. Thus, EtpE-C binding to DNase X drivesEhrlichiaentry by engaging CD147 and hnRNP-K and activating N-WASP-dependent actin polymerization.IMPORTANCEEhrlichia chaffeensis, an obligate intracellular bacterium, causes a blood-borne disease called human monocytic ehrlichiosis, one of the most prevalent life-threatening emerging tick-transmitted infectious diseases in the United States. The survival ofEhrlichiabacteria, and hence, their ability to cause disease, depends on their specific mode of entry into eukaryotic host cells. Understanding the mechanism by whichE. chaffeensisenters cells will create new opportunities for developing effective therapies to prevent bacterial entry and disease in humans. Our findings reveal a novel cellular signaling pathway triggered by an ehrlichial surface protein called EtpE to induce its infectious entry. The results are also important from the viewpoint of human cell physiology because three EtpE-interacting human proteins, DNase X, CD147, and hnRNP-K, are hitherto unknown partners that drive the uptake of small particles, including bacteria, into human cells.

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Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

Journal of Biological Chemistry ◽

10.1074/jbc.m112.443440 ◽

2013 ◽

Vol 288 (29) ◽

pp. 21389-21398 ◽

Cited By ~ 21

Author(s):

Ikuo Nakamura ◽

Maite G. Fernandez-Barrena ◽

Maria C. Ortiz-Ruiz ◽

Luciana L. Almada ◽

Chunling Hu ◽

...

Keyword(s):

Transcription Factor ◽

Wnt Signaling ◽

Cyclin D1 ◽

Signaling Pathways ◽

Tissue Regeneration ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Hepatocyte Proliferation ◽

Dependent Manner ◽

Gli1 Expression

Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.

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Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.00373-15 ◽

2015 ◽

Vol 35 (19) ◽

pp. 3301-3311 ◽

Cited By ~ 35

Author(s):

Jiandang Shi ◽

Yajuan Liu ◽

Xuehe Xu ◽

Wen Zhang ◽

Tianxin Yu ◽

...

Keyword(s):

Gene Expression ◽

Rna Interference ◽

Wnt Signaling ◽

Wnt Pathway ◽

Target Gene ◽

Central Question ◽

Cancer Cell Growth ◽

Positive Role ◽

Content Type

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, whereas β-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47. Finally,in vivostudies in theDrosophilawing suggest that UBP64E, the USP47 counterpart inDrosophila, is required for Armadillo stabilization and plays a positive role in regulating Wnt target gene expression.

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Ehrlichia chaffeensis TRP120 Binds a G+C-Rich Motif in Host Cell DNA and Exhibits Eukaryotic Transcriptional Activator Function

Infection and Immunity ◽

10.1128/iai.05422-11 ◽

2011 ◽

Vol 79 (11) ◽

pp. 4370-4381 ◽

Cited By ~ 36

Author(s):

Bing Zhu ◽

Jeeba A. Kuriakose ◽

Tian Luo ◽

Efren Ballesteros ◽

Sharu Gupta ◽

...

Keyword(s):

Transcriptional Regulation ◽

Dna Binding ◽

Host Cell ◽

High Throughput ◽

Tandem Repeat ◽

Binding Sites ◽

Host Gene ◽

Host Cells ◽

Ehrlichia Chaffeensis ◽

Content Type

ABSTRACTEhrlichia chaffeensisis an obligately intracellular bacterium that modulates host cell gene transcription in the mononuclear phagocyte, but the host gene targets and mechanisms involved in transcriptional modulation are not well-defined. In this study, we identified a novel tandem repeat DNA-binding domain in theE. chaffeensis120-kDa tandem repeat protein (TRP120) that directly binds host cell DNA. TRP120 was observed by immunofluorescent microscopy in the nucleus ofE. chaffeensis-infected host cells and was detected in nuclear extracts by Western immunoblotting with TRP120-specific antibody. The TRP120 binding sites and associated host cell target genes were identified using high-throughput deep sequencing (Illumina) of immunoprecipitated DNA (chromatin immunoprecipitation and high-throughput DNA sequencing). Multiple em motif elicitation (MEME) analysis of the most highly enriched TRP120-bound sequences revealed a G+C-rich DNA motif, and recombinant TRP120 specifically bound synthetic oligonucleotides containing the motif. TRP120 target gene binding sites were mapped most frequently to intersecting regions (intron/exon; 49%) but were also identified in upstream regulatory regions (25%) and downstream locations (26%). Genes targeted by TRP120 were most frequently associated with transcriptional regulation, signal transduction, and apoptosis. TRP120 targeted inflammatory chemokine genes, CCL2, CCL20, and CXCL11, which were strongly upregulated duringE. chaffeensisinfection and were also upregulated by direct transfection with recombinant TRP120. This study reveals that TRP120 is a novel DNA-binding protein that is involved in a host gene transcriptional regulation strategy.

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Misregulation of Wnt Signaling Pathways at the Plasma Membrane in Brain and Metabolic Diseases

Membranes ◽

10.3390/membranes11110844 ◽

2021 ◽

Vol 11 (11) ◽

pp. 844

Author(s):

Mustafa Karabicici ◽

Yagmur Azbazdar ◽

Evin Iscan ◽

Gunes Ozhan

Keyword(s):

Plasma Membrane ◽

Wnt Signaling ◽

Signaling Pathways ◽

Metabolic Diseases ◽

Wnt Signaling Pathway ◽

Membrane Domains ◽

Physiological Processes ◽

Pathway Activation ◽

Wnt Pathways ◽

Membrane Components

Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components—specifically ligands, (co) receptors, and extracellular or membrane-associated modulators—to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt–receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.

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