Rab27b regulates number and secretion of platelet dense granules

Abstract

The Rab27 GTPase subfamily consists of two closely related homologs, Rab27a and Rab27b. Rab27a has been shown previously to regulate organelle movement and regulated exocytosis in a wide variety of secretory cells. However, the role of the more restrictedly expressed Rab27b remains unclear. Here we describe the creation of Rab27b knockout (KO) strain that was subsequently crossed with the naturally occurring Rab27a KO line, ashen, to produce double KO (Rab27a ash/ash Rab27b ؊/؊ ) mice. Rab27b KO (and double KO) exhibit significant hemorrhagic disease in contrast to ashen mice. In vitro assays demonstrated impaired aggregation with collagen and U46619 and reduced secretion of dense granules in both Rab27b and double KO strains. Additionally, we detected a 50% reduction in the number of dense granules per platelet and diminished platelet serotonin content, possibly due to a dense granule packaging defect into proplatelets during megakaryocyte maturation. The presence of Rab27a partially compensated for the secretory defect but not the reduced granule number. The morphology and function of platelet ␣-granules were unaffected. Our data suggest that Rab27b is a key regulator of dense granule secretion in platelets and thus a candidate gene for ␦-storage pool deficiency in humans.membrane traffic ͉ Rab GTPase

Microglial migration mediated by ATP-induced ATP release from lysosomes

“…Furthermore, the migration induced by 0.5 or 0.1 mM ATPγS was dramatically inhibited in Rab27a-deficient microglia ( Figure 7C and 7D), consistent with the important role of Rab27a in the trafficking and exocytosis of lysosomes [9,10]. The result that the microglial migration induced by 1 mM ATPγS was not significantly affected in Rab27a-deficient mice ( Figure 7B) suggest that other subtypes of Rab GTPase, for example Rab27b [28,35,36], may partially compensate for the lysosome deficiency in these mice. Rab27a has been suggested to be associated specifically with secretory lysosomes or lysosome-related organelles in some cells derived from the hematopoietic lineage [9,10], from which microglia are also considered to be derived.…”

The secretory small GTPase Rab27B as a marker for breast cancer progression

“…Interestingly, we found no such effects with Rab27A in vitro and in vivo [3]. Common, but also different nonredundant functions of Rab27A versus Rab27B have been described dependent on the cell type and/or secretory process studied [11][12][13][14]. Interestingly, Wang et al (2008) reported Rab27A-dependent invasion and xenograft metastasis of ER-negative, already invasive, MDA-MB-231 and MDA-MB-435 breast cancer cells.…”

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

“…(51) However, analysis of mice lacking Rab27a and/or Rab27b function has shown that Rab27a and Rab27b appear to have an additive effect on 5-hydroxytriptamine release from platelet dense granules. (52) Also, recent analysis of Rab27a and Rab27b null mice has shown that Rab27a and Rab27b regulate NADPH oxidase release in neutrophils through independent mechanisms. (33) In stimulation-dependent RANKL release in osteoblastic cells, the function of Rab27a and Rab27b does not seem to be redundant because individual knockdown of each of these genes resulted in a significant reduction in RANKL release to the cell surface (Fig.…”