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1.
Cell ; 187(12): 2990-3005.e17, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38772370

RESUMO

Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin ß-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.


Assuntos
Integrinas , Talina , Animais , Humanos , Camundongos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/química , Adesão Celular , Células CHO , Cricetulus , Integrinas/metabolismo , Integrinas/química , Ligantes , Ligação Proteica , Conformação Proteica , Transdução de Sinais , Imagem Individual de Molécula , Talina/metabolismo , Talina/química
2.
Cell ; 187(13): 3445-3459.e15, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38838668

RESUMO

Understanding cellular force transmission dynamics is crucial in mechanobiology. We developed the DNA-based ForceChrono probe to measure force magnitude, duration, and loading rates at the single-molecule level within living cells. The ForceChrono probe circumvents the limitations of in vitro single-molecule force spectroscopy by enabling direct measurements within the dynamic cellular environment. Our findings reveal integrin force loading rates of 0.5-2 pN/s and durations ranging from tens of seconds in nascent adhesions to approximately 100 s in mature focal adhesions. The probe's robust and reversible design allows for continuous monitoring of these dynamic changes as cells undergo morphological transformations. Additionally, by analyzing how mutations, deletions, or pharmacological interventions affect these parameters, we can deduce the functional roles of specific proteins or domains in cellular mechanotransduction. The ForceChrono probe provides detailed insights into the dynamics of mechanical forces, advancing our understanding of cellular mechanics and the molecular mechanisms of mechanotransduction.


Assuntos
Mecanotransdução Celular , Imagem Individual de Molécula , Animais , Humanos , Camundongos , Fenômenos Biomecânicos , Adesão Celular , DNA/química , DNA/metabolismo , Adesões Focais/metabolismo , Integrinas/metabolismo , Microscopia de Força Atômica/métodos , Imagem Individual de Molécula/métodos , Linhagem Celular , Sobrevivência Celular , Pareamento de Bases , Calibragem
3.
Cell ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39288764

RESUMO

TGF-ß, essential for development and immunity, is expressed as a latent complex (L-TGF-ß) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvß8 activates L-TGF-ß1/GARP. The dogma is that mature TGF-ß must physically dissociate from L-TGF-ß1 for signaling to occur. Our previous studies discovered that αvß8-mediated TGF-ß autocrine signaling can occur without TGF-ß1 release from its latent form. Here, we show that mice engineered to express TGF-ß1 that cannot release from L-TGF-ß1 survive without early lethal tissue inflammation, unlike those with TGF-ß1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-ß1 signaling without release where αvß8 binding redistributes the intrinsic flexibility of L-TGF-ß1 to expose TGF-ß1 to its receptors. Dynamic allostery explains the TGF-ß3 latency/activation mechanism and why TGF-ß3 functions distinctly from TGF-ß1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

4.
Cell ; 185(19): 3533-3550.e27, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113427

RESUMO

Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbß3 and α4ß1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbß3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4ß1.


Assuntos
Desenho de Fármacos , Integrina alfa4beta1 , Conformação Proteica , Serina , Água
5.
Annu Rev Cell Dev Biol ; 39: 123-144, 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37315160

RESUMO

Multicellular organisms generate tissues of diverse shapes and functions from cells and extracellular matrices. Their adhesion molecules mediate cell-cell and cell-matrix interactions, which not only play crucial roles in maintaining tissue integrity but also serve as key regulators of tissue morphogenesis. Cells constantly probe their environment to make decisions: They integrate chemical and mechanical information from the environment via diffusible ligand- or adhesion-based signaling to decide whether to release specific signaling molecules or enzymes, to divide or differentiate, to move away or stay, or even whether to live or die. These decisions in turn modify their environment, including the chemical nature and mechanical properties of the extracellular matrix. Tissue morphology is the physical manifestation of the remodeling of cells and matrices by their historical biochemical and biophysical landscapes. We review our understanding of matrix and adhesion molecules in tissue morphogenesis, with an emphasis on key physical interactions that drive morphogenesis.

6.
Cell ; 184(14): 3702-3716.e30, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34133940

RESUMO

Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required ß1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.


Assuntos
Junções Célula-Matriz/metabolismo , Morfogênese , Animais , Membrana Basal/metabolismo , Adesão Celular , Divisão Celular , Movimento Celular , Rastreamento de Células , Embrião de Mamíferos/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Integrinas/metabolismo , Camundongos , Modelos Biológicos , Glândulas Salivares/citologia , Glândulas Salivares/embriologia , Glândulas Salivares/metabolismo , Transcriptoma/genética
7.
Cell ; 184(19): 4919-4938.e22, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34506722

RESUMO

Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.


Assuntos
Capsídeo/metabolismo , Dependovirus/metabolismo , Evolução Molecular Direcionada , Técnicas de Transferência de Genes , Músculo Esquelético/metabolismo , Sequência de Aminoácidos , Animais , Capsídeo/química , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Integrinas/metabolismo , Macaca fascicularis , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/terapia , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/terapia , Multimerização Proteica , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/uso terapêutico , RNA Guia de Cinetoplastídeos/metabolismo , Recombinação Genética/genética , Especificidade da Espécie , Transgenes
8.
Cell ; 181(6): 1346-1363.e21, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32473126

RESUMO

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-ß3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-ß3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell ß3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by ß3-integrin, providing a previously unrecognized mechanism of cancer growth control.


Assuntos
Integrina beta3/metabolismo , Neoplasias/metabolismo , Carga Tumoral/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Humanos , Masculino , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia
9.
Cell ; 180(3): 490-501.e16, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31955848

RESUMO

Integrin αvß8 binds with exquisite specificity to latent transforming growth factor-ß (L-TGF-ß). This binding is essential for activating L-TGF-ß presented by a variety of cell types. Inhibiting αvß8-mediated TGF-ß activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire αvß8 ectodomain and its intact natural ligand, L-TGF-ß, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvß8 binding specificity and TGF-ß activation. Our studies reveal a mechanism of TGF-ß activation where mature TGF-ß signals within the confines of L-TGF-ß and the release and diffusion of TGF-ß are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvß8-mediated L-TGF-ß activation.


Assuntos
Microscopia Crioeletrônica/métodos , Integrinas/química , Integrinas/metabolismo , Proteínas de Ligação a TGF-beta Latente/química , Proteínas de Ligação a TGF-beta Latente/metabolismo , Fator de Crescimento Transformador beta1/química , Fator de Crescimento Transformador beta1/metabolismo , Animais , Anticorpos/imunologia , Sítios de Ligação , Brônquios/citologia , Células CHO , Cricetulus , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Integrinas/imunologia , Ativação Linfocitária , Masculino , Vison , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios e Motivos de Interação entre Proteínas , Linfócitos T Reguladores/imunologia
10.
Cell ; 177(7): 1738-1756.e23, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31104842

RESUMO

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are a major class of lipid-anchored plasma membrane proteins. GPI-APs form nanoclusters generated by cortical acto-myosin activity. While our understanding of the physical principles governing this process is emerging, the molecular machinery and functional relevance of GPI-AP nanoclustering are unknown. Here, we first show that a membrane receptor signaling pathway directs nanocluster formation. Arg-Gly-Asp motif-containing ligands bound to the ß1-integrin receptor activate src and focal adhesion kinases, resulting in RhoA signaling. This cascade triggers actin-nucleation via specific formins, which, along with myosin activity, drive the nanoclustering of membrane proteins with actin-binding domains. Concurrently, talin-mediated activation of the mechano-transducer vinculin is required for the coupling of the acto-myosin machinery to inner-leaflet lipids, thereby generating GPI-AP nanoclusters. Second, we show that these nanoclusters are functional; disruption of their formation either in GPI-anchor remodeling mutants or in vinculin mutants impairs cell spreading and migration, hallmarks of integrin function.


Assuntos
Integrina beta1/metabolismo , Mecanotransdução Celular , Microdomínios da Membrana/metabolismo , Motivos de Aminoácidos , Animais , Células CHO , Cricetulus , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Integrina beta1/genética , Microdomínios da Membrana/genética , Vinculina/genética , Vinculina/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
11.
Immunity ; 57(1): 106-123.e7, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38159573

RESUMO

When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin ß1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.


Assuntos
Cálculos Renais , Rim , Camundongos , Animais , Macrófagos
12.
Cell ; 175(1): 200-211.e13, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30146160

RESUMO

Much of our understanding of chromosome segregation is based on cell culture systems. Here, we examine the importance of the tissue environment for chromosome segregation by comparing chromosome segregation fidelity across several primary cell types in native and nonnative contexts. We discover that epithelial cells have increased chromosome missegregation outside of their native tissues. Using organoid culture systems, we show that tissue architecture, specifically integrin function, is required for accurate chromosome segregation. We find that tissue architecture enhances the correction of merotelic microtubule-kinetochore attachments, and this is especially important for maintaining chromosome stability in the polyploid liver. We propose that disruption of tissue architecture could underlie the widespread chromosome instability across epithelial cancers. Moreover, our findings highlight the extent to which extracellular context can influence intrinsic cellular processes and the limitations of cell culture systems for studying cells that naturally function within a tissue.


Assuntos
Instabilidade Cromossômica/fisiologia , Segregação de Cromossomos/fisiologia , Epitélio/fisiologia , Animais , Agregação Celular/fisiologia , Técnicas de Cultura de Células/métodos , Cromossomos/fisiologia , Células Epiteliais/fisiologia , Feminino , Cinetocoros/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Mitose , Organoides/fisiologia , Fuso Acromático/metabolismo , Fuso Acromático/fisiologia
13.
Cell ; 175(7): 1756-1768.e17, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30550785

RESUMO

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/ß5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Remodelação Óssea , Fibronectinas/metabolismo , Integrina alfaV/metabolismo , Osteócitos/metabolismo , Osteólise/metabolismo , Adipócitos/patologia , Animais , Linhagem Celular Tumoral , Feminino , Fibronectinas/genética , Células HEK293 , Humanos , Integrina alfaV/genética , Camundongos , Osteócitos/patologia , Osteólise/genética
14.
Immunity ; 56(6): 1285-1302.e7, 2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37269830

RESUMO

The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (TRM) cells, but their differentiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family transcription-factor-binding motifs in human epidermal CD8+CD103+CD49a+ TRM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap between epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. In vitro stimulation of circulating CD8+CD45RA-CD62L+ T cells with IL-15 and TGF-ß induced CD49a expression and cytotoxic transcriptional profiles in a RUNX2- and RUNX3-dependent manner. We therefore identified a reservoir of circulating cells with cytotoxic TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malignant cells.


Assuntos
Linfócitos T CD8-Positivos , Melanoma , Humanos , Linfócitos T CD8-Positivos/metabolismo , Integrina alfa1/metabolismo , Integrinas/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Memória Imunológica , Antígenos Comuns de Leucócito/metabolismo , Melanoma/metabolismo
15.
Mol Cell ; 83(11): 1903-1920.e12, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37267907

RESUMO

Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that the extracellular heat shock protein 90α (eHsp90α) is secreted by muscle with exercise and activates integrin αVß5. This allows for high-affinity irisin binding and signaling through an Hsp90α/αV/ß5 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 Å RMSD irisin/αVß5 complex docking model. Irisin binds very tightly to an alternative interface on αVß5 distinct from that used by known ligands. These data elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through an integrin receptor.


Assuntos
Comunicação Celular , Fibronectinas , Humanos , Fibronectinas/metabolismo , Transdução de Sinais
16.
Immunity ; 53(2): 290-302.e6, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32768386

RESUMO

CD47 acts as a "don't eat me" signal that protects cells from phagocytosis by binding and activating its receptor SIPRA on macrophages. CD47 suppresses multiple different pro-engulfment "eat me" signals, including immunoglobulin G (IgG), complement, and calreticulin, on distinct target cells. This complexity has limited understanding of how the "don't eat me" signal is transduced biochemically. Here, we utilized a reconstituted system with a defined set of signals to interrogate the mechanism of SIRPA activation and its downstream targets. CD47 ligation altered SIRPA localization, positioning SIRPA for activation at the phagocytic synapse. At the phagocytic synapse, SIRPA inhibited integrin activation to limit macrophage spreading across the surface of the engulfment target. Chemical reactivation of integrin bypassed CD47-mediated inhibition and rescued engulfment, similar to the effect of a CD47 function-blocking antibody. Thus, the CD47-SIRPA axis suppresses phagocytosis by inhibiting inside-out activation of integrin signaling in the macrophage, with implications to cancer immunotherapy applications.


Assuntos
Antígeno CD47/metabolismo , Integrinas/metabolismo , Macrófagos/imunologia , Fagocitose/imunologia , Receptores Imunológicos/metabolismo , Animais , Calreticulina/imunologia , Linhagem Celular , Proteínas do Sistema Complemento/imunologia , Células HEK293 , Humanos , Imunoglobulina G/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilserinas/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia
17.
Physiol Rev ; 101(1): 319-352, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32584192

RESUMO

The extracellular domain of plasma membrane integrin αvß3 contains a cell surface receptor for thyroid hormone analogues. The receptor is largely expressed and activated in tumor cells and rapidly dividing endothelial cells. The principal ligand for this receptor is l-thyroxine (T4), usually regarded only as a prohormone for 3,5,3'-triiodo-l-thyronine (T3), the hormone analogue that expresses thyroid hormone in the cell nucleus via nuclear receptors that are unrelated structurally to integrin αvß3. At the integrin receptor for thyroid hormone, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis), and angiogenesis and supports metastasis, radioresistance, and chemoresistance. The molecular mechanisms involve signal transduction via mitogen-activated protein kinase and phosphatidylinositol 3-kinase, differential expression of multiple genes related to the listed cell processes, and regulation of activities of other cell surface proteins, such as vascular growth factor receptors. Tetraiodothyroacetic acid (tetrac) is derived from T4 and competes with binding of T4 to the integrin. In the absence of T4, tetrac and chemically modified tetrac also have anticancer effects that culminate in altered gene transcription. Tumor xenografts are arrested by unmodified and chemically modified tetrac. The receptor requires further characterization in terms of contributions to nonmalignant cells, such as platelets and phagocytes. The integrin αvß3 receptor for thyroid hormone offers a large panel of cellular actions that are relevant to cancer biology and that may be regulated by tetrac derivatives.


Assuntos
Integrinas/fisiologia , Hormônios Tireóideos/fisiologia , Animais , Humanos , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Receptores dos Hormônios Tireóideos/fisiologia , Transdução de Sinais , Tiroxina/fisiologia , Tri-Iodotironina
18.
Immunity ; 51(2): 298-309.e6, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31399281

RESUMO

T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin αVß3 expression: Th2 cell differentiation led to high αVß3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of αVß3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of αVß3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.


Assuntos
Inflamação/imunologia , Células Th1/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Técnicas de Reprogramação Celular , Quimiocinas/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT6/metabolismo
19.
Immunity ; 51(3): 479-490.e6, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402259

RESUMO

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.


Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Células NIH 3T3 , Receptores de Interleucina-15/imunologia , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Fator de Crescimento Transformador beta/imunologia
20.
Immunity ; 51(1): 90-103.e3, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31278057

RESUMO

The key sites within the gastrointestinal (GI) tract where T cells mediate effector responses and the impact of these responses on intestinal stem cells (ISCs) remain unclear. Using experimental bone marrow transplantation to model immune-mediated GI damage and 3D imaging to analyze T cell localization, we found that the ISC compartment is the primary intestinal site targeted by T cells after transplantation. Recruitment to the crypt base region resulted in direct T cell engagement with the stem cell compartment and loss of crypt base columnar ISCs, which expressed both MHC classes I and II. Vasculature expressing the adhesion molecule MAdCAM-1 clustered near the crypt base, preferentially regulating crypt compartment invasion and ISC reduction without affecting T cell migration to villi. These findings indicate that allogeneic T cells rapidly access the stem cell niche after transplantation, and this targeted recruitment to the stem cell compartment results in ISC loss during immune-mediated GI damage.


Assuntos
Células-Tronco Adultas/imunologia , Transplante de Medula Óssea , Mucosa Intestinal/imunologia , Nicho de Células-Tronco/imunologia , Linfócitos T/imunologia , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Moléculas de Adesão Celular/metabolismo , Movimento Celular , Citotoxicidade Imunológica , Feminino , Humanos , Imageamento Tridimensional , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Modelos Animais , Mucoproteínas , Transplante Homólogo
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