Dataset Information

Rab46 integrates Ca²⁺ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

ABSTRACT: Endothelial cells selectively release cargo stored in Weibel-Palade bodies (WPBs) to regulate vascular function, but the underlying mechanisms are poorly understood. Here we show that histamine evokes the release of the proinflammatory ligand, P-selectin, while diverting WPBs carrying non-inflammatory cargo away from the plasma membrane to the microtubule organizing center. This differential trafficking is dependent on Rab46 (CRACR2A), a newly identified Ca²⁺-sensing GTPase, which localizes to a subset of P-selectin-negative WPBs. After acute stimulation of the H₁ receptor, GTP-bound Rab46 evokes dynein-dependent retrograde transport of a subset of WPBs along microtubules. Upon continued histamine stimulation, Rab46 senses localized elevations of intracellular calcium and evokes dispersal of microtubule organizing center-clustered WPBs. These data demonstrate for the first time that a Rab GTPase, Rab46, integrates G protein and Ca²⁺ signals to couple on-demand histamine signals to selective WPB trafficking.

SUBMITTER: Miteva KT

PROVIDER: S-EPMC6605797 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rab46 integrates Ca<sup>2+</sup> and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Miteva Katarina T KT Pedicini Lucia L Wilson Lesley A LA Jayasinghe Izzy I Slip Raphael G RG Marszalek Katarzyna K Gaunt Hannah J HJ Bartoli Fiona F Deivasigamani Shruthi S Sobradillo Diego D Beech David J DJ McKeown Lynn L

The Journal of cell biology 20190515 7

Endothelial cells selectively release cargo stored in Weibel-Palade bodies (WPBs) to regulate vascular function, but the underlying mechanisms are poorly understood. Here we show that histamine evokes the release of the proinflammatory ligand, P-selectin, while diverting WPBs carrying non-inflammatory cargo away from the plasma membrane to the microtubule organizing center. This differential trafficking is dependent on Rab46 (CRACR2A), a newly identified Ca<sup>2+</sup>-sensing GTPase, which loc ...[more]

PMID: 31092558

Similar Datasets

Project description:Essentials Endothelial activation initiates multiple processes, including hemostasis and inflammation. The molecules that contribute to these processes are co-stored in secretory granules. How can the cells control release of granule content to allow differentiated responses? Selected agonists recruit an exocytosis-linked actin ring to boost release of a subset of cargo.SummaryBackground Endothelial cells harbor specialized storage organelles, Weibel-Palade bodies (WPBs). Exocytosis of WPB content into the vascular lumen initiates primary hemostasis, mediated by von Willebrand factor (VWF), and inflammation, mediated by several proteins including P-selectin. During full fusion, secretion of this large hemostatic protein and smaller pro-inflammatory proteins are thought to be inextricably linked. Objective To determine if secretagogue-dependent differential release of WPB cargo occurs, and whether this is mediated by the formation of an actomyosin ring during exocytosis. Methods We used VWF string analysis, leukocyte rolling assays, ELISA, spinning disk confocal microscopy, high-throughput confocal microscopy and inhibitor and siRNA treatments to demonstrate the existence of cellular machinery that allows differential release of WPB cargo proteins. Results Inhibition of the actomyosin ring differentially effects two processes regulated by WPB exocytosis; it perturbs VWF string formation but has no effect on leukocyte rolling. The efficiency of ring recruitment correlates with VWF release; the ratio of release of VWF to small cargoes decreases when ring recruitment is inhibited. The recruitment of the actin ring is time dependent (fusion events occurring directly after stimulation are less likely to initiate hemostasis than later events) and is activated by protein kinase C (PKC) isoforms. Conclusions Secretagogues differentially recruit the actomyosin ring, thus demonstrating one mechanism by which the prothrombotic effect of endothelial activation can be modulated. This potentially limits thrombosis whilst permitting a normal inflammatory response. These results have implications for the assessment of WPB fusion, cargo-content release and the treatment of patients with von Willebrand disease.

Dataset Information

Rab46 integrates Ca²⁺ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Publications

Rab46 integrates Ca<sup>2+</sup> and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Rab46 integrates Ca2+ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Publications

Rab46 integrates Ca&lt;sup&gt;2+&lt;/sup&gt; and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Rab46 integrates Ca²⁺ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Rab46 integrates Ca<sup>2+</sup> and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.