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**3** 

*USA* 

**Phosphatidylinositol Bisphosphate** 

Douglas S. Darling, Srirangapatnam G. Venkatesh,

Dipti Goyal and Anne L. Carenbauer *University of Louisville, Louisville, Kentucky* 

**Mediated Sorting of Secretory Granule Cargo** 

Every cell must sort and transport proteins. This is true for soluble proteins as well as proteins that are in membranes, each of which need to be directed to appropriate subcellular or extracellular destinations in order to perform their essential functions. In eukaryotes, selective trafficking contributes to maintaining the different compositions of different membranes such as apical and basolateral plasma membranes, as well as directing appropriate proteins to lysosomes, endosomes, multivesicular bodies, or other intracellular compartments. The normal physiology of the cell is critically dependent on selective trafficking of proteins and membranes between different transport pathways within the cell. Other chapters in this book focus on the mechanics of transporting cargo membranes, including the molecular aspects of vesicle fusion to specific target membranes. This chapter will focus on the importance and mechanisms of sorting luminal cargo into different pathways, i.e., the "selective" aspect of selective trafficking, particularly with respect to

Selective trafficking of new proteins is largely achieved by budding of vesicles from the trans-Golgi network (TGN) for transport to specific organelles or to specific regions of the plasmalemma. Different terminology is used for these vesicles depending on their size, histological appearance, contents, or cell type. Granules (including dense-core secretory granules, DCSG) are secretory vesicles present in endocrine, exocrine, immune, and neuroendocrine cells, responsible for both storage and secretion of proteins. Lymphocytes, dendritic cells, and natural killer cells also contain secretory lysosomes for the release of lysosomal enzymes (Stanley and Lacy 2010), and neurons contain peptidergic synaptic vesicles (Park and Loh 2008; Park et al. 2011). However, all of these types of vesicles serve the same broad purpose of transporting specific cargo to specific destinations by an

The lipid membranes of these vesicles carry tightly associated cytoplasmic proteins (termed coat proteins) which not only help form the vesicle, but also direct the vesicle to the correct destination (De Matteis and Luini 2008; Santiago-Tirado and Bretscher 2011; Wilson et al. 2011). The matrix of coat proteins on the cytosolic face of the membrane contributes to the bending of the TGN membrane during budding of the vesicle. This matrix is formed by multiple interactions, including binding of coat proteins to phosphatidylinositol phosphates

**1. Introduction** 

exocrine secretion.

appropriately regulated pathway.

