**7. Concluding remarks**

Here we have illustrated that there is a complex array of specialist molecular machinery that is used to control each step in the process of exocytosis. Emerging evidence suggests that there is a highly organised regulatory network required to achieve control of exocytosis. This involves the post-translational modification of the vesicular machinery and membrane associated proteins that orchestrate exocytosis; including the addition of lipid moieties, phosphorylation, and ubiquitination and sumoylation. These post-translational modifications are responsible for mediating protein intracellular localization, proteinprotein interactions, complex assembly, and ultimately protein function. The dynamics and precision of exocytosis often require multiple modifications of a single protein in order to tightly control temporal/spatial function. Moreover, to ensure the harmonious reaction of the cell to a specific stimulation, these post-translational modifications respond to a variety of cell-type specific signaling events. The challenge facing researchers in this field is to investigate the cross-talk between different modifications in the context of a specific signal, and to determine how these are coordinated with other cellular functions. Thus, it is tempting to speculate about an even higher point of control in the regulation of exocytosis, involving proteins that recognise post-translational modifications and facilitate appropriate functional interaction.

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**5** 

**At the Intersection of the Pathways** 

**for Exocytosis and Autophagy** 

*Mechanisms in Cell Biology and Diseases Research Group,* 

*School of Pharmacy and Medical Sciences, Sansom Institute for Health Research* 

Recent studies have suggested that there are molecular links between the two critical biological processes of exocytosis and autophagy. Exocytosis involves the transport of intracellular vesicles to the plasma membrane of the cell, where vesicular fusion results in the delivery of membrane and protein to the cell surface, and secretion of the vesicular contents. Exocytosis is utilized in, for example, hormone or antimicrobial peptide secretion, the delivery of proteoglycans to the cell surface, cell-cell communication and neurotransmission (Brennwald & Rossi, 2007; He & Guo, 2009). Autophagy is a mechanism for the recycling and degradation of cytoplasmic content, which involves surrounding an area of cytoplasm with a double membrane structure, which then interacts with degradative endosome-lysosome compartments (He & Klionsky, 2009). Autophagy has important functions in a range of cell processes including the maintenance of cellular homeostasis, starvation adaption, energy balance, organelle clearance, immunity and cell death. In human diseases, such as cancers, neurodegenerative disorders (e.g. Huntington's disease), and chronic inflammatory diseases (e.g. Crohn's disease), there have been reports of functional disparity in both of these important membrane-related cellular pathways. There is now increasing evidence that exocytosis and autophagy share molecular machinery and there are a number of reasons why this would be beneficial in terms of cellular function.

Exocytosis and autophagy may be competitively, cooperatively or independently regulated, depending upon the nature of the intracellular and/or extracellular environment. In response to conditions of low or high energy demand, there would be an advantage to the cell in reducing the energy consuming process of secretion, where the membrane from exocytic vesicles could be utilized to enable rapid expansion of the autophagic compartment (i.e. competitive regulation). During an immune response there may be concomitant stimulation of autophagy to degrade an intracellular bacterial pathogen, and exocytosis to release second messengers and antimicrobial effectors. Alternatively, it may be necessary to only upregulate an individual process, which is the case for increased autophagy during organelle and cytoplasm turnover under restricted nutrient supply (e.g. in the bone growth plate) (He & Klionsky, 2009), or increased exocytosis during proteoglycan delivery to the

**1. Introduction** 

R.D. Brooks, G.N. Borlace and T. Shandala

D.A. Brooks, C. Bader, Y.S. Ng,

*University of South Australia* 

*Australia* 

neuronal excitation in vivo. *Journal of neurochemistry*. Vol. 80, No.5 (March 2002), pp.835-842, 0022-3042

