The Exocyst Protein Sec10 Interacts with Polycystin-2 and Knockdown Causes PKD-Phenotypes

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of renal cysts that destroy the kidney. Mutations in PKD1 and PKD2, encoding polycystins-1 and -2, cause ADPKD. Polycystins are thought to function in primary cilia, but it is not well understood how these and other proteins are targeted to cilia. Here, we provide the first genetic and biochemical link between polycystins and the exocyst, a highly-conserved eight-protein membrane trafficking complex. We show that knockdown of exocyst component Sec10 yields cellular phenotypes associated with ADPKD, including loss of flow-generated calcium increases, hyperproliferation, and abnormal activation of MAPK. Sec10 knockdown in zebrafish phenocopies many aspects of polycystin-2 knockdown—including curly tail up, left-right patterning defects, glomerular expansion, and MAPK activation—suggesting that the exocyst is required for pkd2 function in vivo. We observe a synergistic genetic interaction between zebrafish sec10 and pkd2 for many of these cilia-related phenotypes. Importantly, we demonstrate a biochemical interaction between Sec10 and the ciliary proteins polycystin-2, IFT88, and IFT20 and co-localization of the exocyst and polycystin-2 at the primary cilium. Our work supports a model in which the exocyst is required for the ciliary localization of polycystin-2, thus allowing for polycystin-2 function in cellular processes

Claudins in lung diseases

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development

The Politics of Multi-Stakeholder Initiatives: The Crisis of the Forest Stewardship Council

Multi-stakeholder initiatives (MSIs) have become a vital part of the organizational landscape for corporate social responsibility. Recent debates have explored whether these initiatives represent opportunities for the ?democratization? of transnational corporations, facilitating civic participation in the extension of corporate responsibility, or whether they constitute new arenas for the expansion of corporate influence and the private capture of regulatory power. In this article, we explore the political dynamics of these new governance initiatives by presenting an in-depth case study of an organization often heralded as a model MSI: the Forest Stewardship Council (FSC). An effort to address global deforestation in the wake of failed efforts to agree a multilateral convention on forests at the Rio Summit (UNCED) in 1992, the FSC was launched in 1993 as a non-state regulatory experiment: a transnational MSI, administering a global eco-labeling scheme for timber and forest products. We trace the scheme?s evolution over the past two decades, showing that while the FSC has successfully facilitated multi-sectoral determination of new standards for forestry, it has nevertheless failed to transform commercial forestry practices or stem the tide of tropical deforestation. Applying a neo-Gramscian analysis to the organizational evolution of the FSC, we examine how broader market forces and resource imbalances between non-governmental and market actors can serve to limit the effectiveness of MSIs in the current neo-liberal environment. This presents dilemmas for NGOs which can lead to their defection, ultimately undermining the organizational legitimacy of MSIs