Physiological Roles of Rab27 Effectors in Regulated Exocytosis

Abstract

Abstract. Recent discoveries that Rab27a/b and their multiple effectors are involved in the regulated exocytosis of lysosome-related organelles and secretory granules have generated numerous related studies. However, not all of these studies have yielded physiologically relevant data because they were not all performed under physiological conditions. For example, "in vivo interactions" have been claimed without examination of the endogenous complex. In some studies, the only proof of interaction was between exogenously expressed proteins in cultured cells where these proteins are not normally expressed. Because regulated exocytic pathways contain highly differentiated secretory organelles, it is important to analyze the molecular interaction in cells harboring these organelles and the associated molecules. Furthermore, previous overexpression experiments to examine the effect on secretion often failed to compare the level of the exogenous protein with that of the endogenous one. Similarly, some knockdown experiments using small-interfering RNAs have only shown downregulation of the exogenously expressed protein, and not of the endogenous one. Many of the conflicting findings in previous studies may be attributable to these shortcomings. The present study summarizes our knowledge about the roles of Rab27 effectors in regulated exocytic pathways based on physiologically relevant data.

Rab2a and Rab27a cooperatively regulate the transition from granule maturation to exocytosis through the dual effector Noc2

“…Furthermore, mice deficient in these proteins exhibit defects in granule biogenesis and/or maturation (Cao et al, 2013;Holst et al, 2013). On the other hand, Rab27a associates with secretory granules (Yi et al, 2002) and regulates the late steps of granule exocytosis, such as recruitment and/or docking to fusion sites, through its multiple effector proteins (Izumi, 2007(Izumi, , 2011. Consistent with this, we found that knockdown of Rab2a or ICA69 inhibits insulin synthesis and processing, whereas that of Rab27a primarily affects insulin secretion.…”

Cdx2 regulates endo-lysosomal function and epithelial cell polarity

“…7E). However, suppression of Rab27a, a Rab GTPase involved in exocytosis of lysosome-related organelles and secretory granules (Izumi 2007), had little effect on lumen formation in the cyst assay (Fig. 7C).…”

Exosome signaling in mammary gland development and cancer

“…dense cored secretory granules in PC12 cells, and late endosome/lysosome related secretory granules e.g. melanosomes in melanocytes, lytic granules in T lymphocytes, MIIC in dendritic cells (Izumi, 2007). Using a semi-quantitative FACS-based assay of exosome secretion from HeLa cells stably expressing transactivator CIITA (an activator of the MHC class II family genes, including HLA-DR-marker of exosomes) and a secreted form of chicken ovalbumin (marker of the constitutive secretory pathway), they found that RNAi knockdown of several Rabs, including Rab27A and Rab27B, resulted in a specific reduction in exosome secretion.…”