Constitutive secretion is responsible for the targeting of transmembrane proteins to the plasma membrane, and for the secretion of extracellular matrix proteins, hormones, and other cellular products. The basic steps of secretion are well understood – proteins synthesized in the endoplasmic reticulum are transported in lipid-bound intermediates to the Golgi, and from the Golgi to the plasma membrane or cell exterior. Dysfunction of the secretory pathway – either constitutive or regulated – is involved in many disease states.
One such state is diabetic nephropathy (DN). DN is characterized by renal hypertrophy and fibrosis, and is the leading cause of renal failure worldwide. Our lab had previously shown that munc13 is both upregulated and activated in the diabetic kidney, and that munc13 is an effector of rab34. Study of rab34 in HeLa cells revealed that rab34 is localized to the Golgi, and that it is required for the secretion of the Vesicular Stomatitis Virus glycoprotein. Colocalization experiments, as well as the use of Brefeldin A, localized the effect of rab34 to intra-Golgi transport. Further experiments indicated that glucose-induced upregulation of munc13 in rat mesangial cells increased the rate of constitutive secretion to the plasma membrane, and that this effect depended on its interaction with rab34. Finally, munc13 and rab34 were found to be required for the high glucose-mediated stimulation of Transforming Growth Factor-β secretion from mesangial cells, placing these two proteins at a key point in a pathway of physiological significance in the pathology of DN.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17766 |
| Date | 24 September 2009 |
| Creators | Goldenberg, Neil Michael |
| Contributors | Silverman, Mel |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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