Roles moleculaires des proteines de choc thermique dans le fonctionnement des organismes a des temperatures normales et suite a des chocs thermiques; differents genes impliques

The heat-shock proteins

In the cell, as in vitro, the final conformation of a protein is determined by its amino-acid sequence. But whereas some isolated proteins can be denatured and refolded in vitro in the absence of other macromolecular cellular components, folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.

Protein folding in the cell.

Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.

http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Biochemistry/Interferons.pdf

How cells respond to interferons

The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.

Regulated portals of entry into the cell

Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.

Strategies in the design of nanoparticles for therapeutic applications

The ability of cancer cells to degrade the extracellular matrix and invade interstitial tissues contributes to their metastatic potential. We recently showed that overexpression of sorting nexin 9 (SNX9) leads to increased cell invasion and metastasis in animal models, which correlates with increased SNX9 protein expression in metastases from human mammary cancers. Here, we report that SNX9 expression is reduced relative to neighboring normal tissues in primary breast tumors, and progressively reduced in more aggressive stages of non-small-cell lung cancers. We show that SNX9 is localized at invadopodia where it directly binds the invadopodia marker TKS5 and negatively regulates invadopodia formation and function. SNX9 depletion increases invadopodia number and the local recruitment of MT1-MMP by decreasing its internalization. Together, these effects result in increased localized matrix degradation. We further identify SNX9 as a Src kinase substrate and show that this phosphorylation is important for SNX9 activity in regulating cell invasion, but is dispensable for its function in regulating invadopodia. The diversified changes associated with SNX9 expression in cancer highlight its importance as a central regulator of cancer cell behavior.

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

Transport vesicles that bud from one cell membrane must change identity before fusing with another During the process of clathrin-mediated endocytosis, various lipid phosphates mediate this identity change See Letter p233
 Phosphoinositides are important regulators of intracellular membrane traffic Although the role of phosphatidylinositol-4,5-bisphosphate has been well characterized, that of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) remains unclear In this study, Volker Haucke and colleagues show that formation of PI(3,4)P2 by the class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) enzyme spatiotemporally controls clathrin-mediated endocytosis These findings present a novel function of PI(3,4)P2 in membrane traffic

Cell biology: Lipid switches and traffic control

Every organelle in a eukaryotic cell contains enzymes with specialized functions, unique to that organelle. But the endosome does things differently — it is regulated, in part, by a unique lipid called lysobisphosphatidic acid (LBPA). This lipid seems to be crucial, because anti-LBPA antibodies affect both the structure and function of the late endosome. Moreover, LBPA is recognized by autoimmune sera from patients with antiphospholipid syndrome, indicating that it may be involved in pathogenesis of this disease.

Membrane sorting: Endosome marker is fat not fiction

Dynamin GTPases (Dyn1 and Dyn2) are indispensable proteins of the core clathrin-mediated endocytosis (CME) machinery Best known for their role in fission at the late stages of CME, many studies have suggested that dynamin also plays a regulatory role during the early stages of CME; however, detailed studies regarding isoform-specific early regulatory functions of the dynamins are lacking With a recent understanding of the regulation of Dyn1 in nonneuronal cells and improved algorithms for highly sensitive and quantitative analysis of clathrin-coated pit (CCP) dynamics, we have evaluated the differential functions of dynamin isoforms in CME using domain swap chimeras We report that Dyn1 and Dyn2 play nonredundant, early regulatory roles during CME in nonneuronal cells The proline/arginine-rich domain of Dyn2 is important for its targeting to nascent and growing CCPs, whereas the membrane-binding and curvature-generating pleckstrin homology domain of Dyn1 plays an important role in stabilizing nascent CCPs We confirm the enhanced ability of dephosphorylated Dyn1 to support CME, even at substoichiometric levels compared with Dyn2 Domain swap chimeras also revealed previously unknown functional differences in the GTPase and stalk domains Our study significantly extends the current understanding of the regulatory roles played by dynamin isoforms during early stages of CME

/pdf/early-and-nonredundant-functions-of-dynamin-isoforms-in-2bovcerjnx.pdf

Early and nonredundant functions of dynamin isoforms in clathrin-mediated endocytosis.

We have developed a new rapid cell-free assay for endocytic clathrin-coated vesicle formation using highly purified rat liver plasma membrane sheets. After incubation in the presence of cytosol and nucleotides, released vesicles were collected by high-speed centrifugation and incorporated cargo receptors were detected by Western blotting. Three different cargo receptors were internalized into vesicles while a receptor, known to be excluded from coated pits, was not. The recruitment of cargo receptors into the vesicle fraction was cytosol, ATP and temperature-dependent and was enhanced by addition of GTP. Vesicle formation in this assay was confirmed by subcellular fractionation and EM analysis. Plasma membranes stripped of their endogenous coat proteins with 0.5 m Tris retained vesicle formation activity, which was highly dependent on clathrin and dynamin. Coat proteins and dynamin were not sufficient for clathrin-coated vesicle formation, and other peripheral membrane proteins recruited from the cytosol are required. The nonhydrolyzable ATP analogue, AMPPNP did not support clathrin-coated vesicle formation; however, surprisingly, GTPγS was as effective as GTP. This assay will provide a powerful tool to dissect the minimum machinery and to probe the hierarchy of events involved in cargo selection and endocytic clathrin-coated vesicle formation.

Sandra L. Schmid

Papers

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

Cell biology: Lipid switches and traffic control

Membrane sorting: Endosome marker is fat not fiction

Early and nonredundant functions of dynamin isoforms in clathrin-mediated endocytosis.

Clathrin- and dynamin-dependent coated vesicle formation from isolated plasma membranes.