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1.
J Immunol ; 203(9): 2377-2387, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31548330

RESUMO

Flotillin-1 (Flot1) is an evolutionary conserved, ubiquitously expressed lipid raft-associated scaffolding protein. Migration of Flot1-deficient neutrophils is impaired because of a decrease in myosin II-mediated contractility. Flot1 also accumulates in the uropod of polarized T cells, suggesting an analogous role in T cell migration. In this study, we analyzed morphology and migration parameters of murine wild-type and Flot1-/- CD8+ T cells using in vitro assays and intravital two-photon microscopy of lymphoid and nonlymphoid tissues. Flot1-/- CD8+ T cells displayed significant alterations in cell shape and motility parameters in vivo but showed comparable homing to lymphoid organs and intact in vitro migration to chemokines. Furthermore, their clonal expansion and infiltration into nonlymphoid tissues during primary and secondary antiviral immune responses was comparable to wild-type CD8+ T cells. Taken together, Flot1 plays a detectable but unexpectedly minor role for CD8+ T cell behavior under physiological conditions.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/fisiologia , Animais , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Epiderme/imunologia , Feminino , Memória Imunológica , Ativação Linfocitária , Masculino , Microdomínios da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
2.
Mol Biol Cell ; 25(5): 583-93, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24403604

RESUMO

Tissue fibrosis occurs when matrix production outpaces matrix degradation. Degradation of collagen, the main component of fibrotic tissue, is mediated through an extracellular proteolytic pathway and intracellular pathway of cellular uptake and lysosomal digestion. Recent studies demonstrate that disruption of the intracellular pathways can exacerbate fibrosis. These pathways are poorly characterized. Here we identify novel mediators of the intracellular pathway of collagen turnover through a genome-wide RNA interference screen in Drosophila S2 cells. Screening of 7505 Drosophila genes conserved among metazoans identified 22 genes that were required for efficient internalization of type I collagen. These included proteins involved in vesicle transport, the actin cytoskeleton, and signal transduction. We show further that the flotillin genes have a conserved and central role in collagen uptake in Drosophila and human cells. Short hairpin RNA-mediated silencing of flotillins in human monocyte and fibroblasts impaired collagen uptake by promoting lysosomal degradation of the endocytic collagen receptors uPARAP/Endo180 and mannose receptor. These data provide an initial characterization of intracellular pathways of collagen turnover and identify the flotillin genes as critical regulators of this process. A better understanding of these pathways may lead to novel therapies that reduce fibrosis by increasing collagen turnover.


Assuntos
Colágeno/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila/genética , Proteínas de Membrana/fisiologia , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Técnicas de Silenciamento de Genes , Genoma de Inseto , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Interferência de RNA
3.
J Cell Biol ; 191(4): 771-81, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21059848

RESUMO

We studied the function of plasma membrane microdomains defined by the proteins flotillin 1 and flotillin 2 in uropod formation and neutrophil chemotaxis. Flotillins become concentrated in the uropod of neutrophils after exposure to chemoattractants such as N-formyl-Met-Leu-Phe (fMLP). Here, we show that mice lacking flotillin 1 do not have flotillin microdomains, and that recruitment of neutrophils toward fMLP in vivo is reduced in these mice. Ex vivo, migration of neutrophils through a resistive matrix is reduced in the absence of flotillin microdomains, but the machinery required for sensing chemoattractant functions normally. Flotillin microdomains specifically associate with myosin IIa, and spectrins. Both uropod formation and myosin IIa activity are compromised in flotillin 1 knockout neutrophils. We conclude that the association between flotillin microdomains and cortical cytoskeleton has important functions during neutrophil migration, in uropod formation, and in the regulation of myosin IIa.


Assuntos
Extensões da Superfície Celular/metabolismo , Quimiotaxia de Leucócito/fisiologia , Citoesqueleto/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Neutrófilos/fisiologia , Animais , Células HeLa , Humanos , Microdomínios da Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Espectrina/metabolismo
4.
Trends Cell Biol ; 20(4): 177-86, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20153650

RESUMO

Caveolae are ampullate (flask-shaped) invaginations that are abundant in the plasma membrane of many mammalian cell types. Although caveolae are implicated in a wide range of processes including endothelial transcytosis, lipid homeostasis and cellular signalling, a detailed molecular picture of many aspects of their function has been elusive. Until recently, the only extensively characterised protein components of caveolae were the caveolins. Recently, data from several laboratories have demonstrated that a family of four related proteins, termed cavins 1-4, plays key roles in caveolar biogenesis and function. Salient properties of the cavin family include their propensity to form complexes with each other and their different but overlapping tissue distribution. This review summarises recent data on the cavins, and sets them in the context of open questions on the construction and function of caveolae. The discovery of cavins implies that caveolae might have unexpectedly diverse structural properties, in accord with the wide range of functions attributed to these 'little caves'.


Assuntos
Cavéolas/metabolismo , Caveolinas/metabolismo , Proteínas de Membrana/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Membrana Celular/ultraestrutura , Regulação da Expressão Gênica , Células HeLa , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Proteínas de Ligação a RNA
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