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Review
. 2021 Nov 6;46(2):79-94.
doi: 10.1247/csf.21043. Epub 2021 Sep 4.

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Tetsuro Izumi  1
Affiliations
Review

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Tetsuro Izumi. Cell Struct Funct. .

Abstract

The monomeric GTPase Rab27 regulates exocytosis of a broad range of vesicles in multicellular organisms. Several effectors bind GTP-bound Rab27a and/or Rab27b on secretory vesicles to execute a series of exocytic steps, such as vesicle maturation, movement along microtubules, anchoring within the peripheral F-actin network, and tethering to the plasma membrane, via interactions with specific proteins and membrane lipids in a local milieu. Although Rab27 effectors generally promote exocytosis, they can also temporarily restrict it when they are involved in the rate-limiting step. Genetic alterations in Rab27-related molecules cause discrete diseases manifesting pigment dilution and immunodeficiency, and can also affect common diseases such as diabetes and cancer in complex ways. Although the function and mechanism of action of these effectors have been explored, it is unclear how multiple effectors act in coordination within a cell to regulate the secretory process as a whole. It seems that Rab27 and various effectors constitutively reside on individual vesicles to perform consecutive exocytic steps. The present review describes the unique properties and in vivo roles of the Rab27 system, and the functional relationship among different effectors coexpressed in single cells, with pancreatic beta cells used as an example.Key words: membrane trafficking, regulated exocytosis, insulin granules, pancreatic beta cells.

Keywords: insulin granules; membrane trafficking; pancreatic beta cells; regulated exocytosis.

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Figures

Fig. 1
Fig. 1
Schematic structures of Rab27 effectors. The Rab-binding domain (pink) with or without a zinc finger domain (light purple) binds Rab27, although that of rabphilin, granuphilin, or Noc2 also shows affinities to Rab3 and Rab8. Noc2 also binds Rab2a at the N-terminal region only in the presence of Rab27a. Asterisk indicates the unique Rab27 binding site of Munc13-4. The amino acid (AA) numbers on the right are those of mouse gene products.
Fig. 2
Fig. 2
Insulin granule exocytosis in a monolayer of mouse pancreatic islet cells expressing insulin-enhanced green fluorescent protein under TIRF microscopy. Fused insulin granules imaged by TIRF microscopy are categorized into three types: residents, visitors, and passengers, depending on their distinct prefusion behaviors. Shown are examples of residents, visitors, and passengers, which morphologically represent granules that fuse with docking before stimulation, docking during stimulation, and without stable docking, to the plasma membrane, respectively. See (Wang et al., 2020) for criteria of the categorization. Note that morphological docking under TIRF microscopy does not necessarily indicate the molecular tethering of granules to the plasma membrane. Sequential images were acquired every 103 milliseconds. The white boxes indicate the time of the beginning of fusion. Bar, 1 μm.
Fig. 3
Fig. 3
Distinct insulin granule exocytic steps regulated by different Rab27 effectors in pancreatic beta cells. Noc2 is postulated to regulate granule maturation. Exophilin-8 anchors granules in the peripheral actin network and may mediate subsequent granule exocytosis with or without granule docking to the plasma membrane. Exophilin-7 and melanophilin mediate undocked granule exocytosis, probably by different routes and mechanisms. Granuphilin mediates docked granule exocytosis. Arrows indicate some possible serial orders in which these effectors act on individual granules, although this has yet to be confirmed empirically.
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