Affinity-based proteomics reveals novel binding partners for Rab46 in endothelial cells

Pedicini, Lucia; Wiktor, Sabina D; Simmons, Katie J.; Money, Ashley; McKeown, Lynn

doi:10.1038/s41598-021-83560-y

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…Rab4a strongly recruited Rab6 (Rab6A:Rab6B:Rab39; protein group not distinguishable by MS/MS) and Rab7a, suggesting interplay between these trafficking routes (Figure 2). Furthermore, Rab11a and Rab25 recruited the related GTPases Arl13b (Figure 2), RABL6 (longlist only, Supplementary Table 2) and CRACR2A (Rab46), a dynein adaptor which can play a role in the stimulated release of Weibel-Palade bodies in endothelial cells (Miteva et al, 2019; Pedicini et al, 2021; Wang et al, 2019). Taken together these data give confidence that BioID is an excellent technique to capture and compare Rab interactions in live cells.…”

Section: Resultsmentioning

confidence: 99%

Proximity labelling identifies pro-migratory endocytic recycling cargo and machinery of the Rab4 and Rab11 families

Wilson

Gemperle

Lawless

et al. 2022

Preprint

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Endocytic recycling controls the return of internalised cargos to the plasma membrane to coordinate their positioning, availability and downstream signalling. The Rab4 and Rab11 small GTPase families regulate distinct recycling routes, broadly classified as fast recycling from early endosomes (Rab4) and slow recycling from perinuclear recycling endosomes (Rab11), and both routes handle a broad range of overlapping cargos to regulate cell behaviour. We adopted a proximity labelling approach, BioID, to identify and compare the protein complexes recruited by Rab4a, Rab11a and Rab25 (a Rab11 family member implicated in cancer aggressiveness), revealing statistically robust protein-protein interaction networks of both new and well characterised cargos and trafficking machinery in migratory cancer cells. Gene ontological analysis of these interconnected networks revealed that these endocytic recycling pathways are intrinsically connected to cell motility and cell adhesion. Using a knock sideways relocalisation approach we were further able to confirm novel links between Rab11/25 and the ESCPE-1 and retromer multiprotein sorting complexes and identify new endocytic recycling machinery associated with Rab4, Rab11 and Rab25 that regulates cancer cell migration in 3D-matrix.

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Section: Resultsmentioning

confidence: 99%

Proximity labelling identifies pro-migratory endocytic recycling cargo and machinery of the Rab4 and Rab11 families

Wilson

Gemperle

Lawless

et al. 2022

Preprint

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“…Rab45 and Rab46 contain two EFDs (Figure 1). The second EFD of Rab46 reportedly binds to Ca 2+ [23,24]. The EFDs of Rab45 have not been investigated.…”

Section: Common Features Of Large Rab Gtpasesmentioning

confidence: 99%

“…The PRD of Rab46 associates with the SH3-SH2-SH3 domains of Vav1, wherein Vav1 is tyrosine-phosphorylated after TCR stimulation [35]. Recently, it has been found that Rab46 directly binds to the motor protein dynein-dynactin complex [24,25,58], and the Na 2+ /K + ATPase subunit alpha 1 in endothelial cells [24].…”

Section: Binding Molecules And/or Effectorsmentioning

confidence: 99%

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Tsukuba

Yamaguchi

Kadowaki

2021

IJMS

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Rab GTPases are major coordinators of intracellular membrane trafficking, including vesicle transport, membrane fission, tethering, docking, and fusion events. Rab GTPases are roughly divided into two groups: conventional “small” Rab GTPases and atypical “large” Rab GTPases that have been recently reported. Some members of large Rab GTPases in mammals include Rab44, Rab45/RASEF, and Rab46. The genes of these large Rab GTPases commonly encode an amino-terminal EF-hand domain, coiled-coil domain, and the carboxyl-terminal Rab GTPase domain. A common feature of large Rab GTPases is that they express several isoforms in cells. For instance, Rab44’s two isoforms have similar functions, but exhibit differential localization. The long form of Rab45 (Rab45-L) is abundantly distributed in epithelial cells. The short form of Rab45 (Rab45-S) is predominantly present in the testes. Both Rab46 (CRACR2A-L) and the short isoform lacking the Rab domain (CRACR2A-S) are expressed in T cells, whereas Rab46 is only distributed in endothelial cells. Although evidence regarding the function of large Rab GTPases has been accumulating recently, there are only a limited number of studies. Here, we report the recent findings on the large Rab GTPase family concerning their function in membrane trafficking, cell differentiation, related diseases, and knockout mouse phenotypes.

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“…1a ) [ 8 ]. Rab46 is necessary for stimuli-coupled trafficking of a sub-population of endothelial-specific vesicles to the microtubule organizing center [ 9 , 10 ] and for vesicle translocation to the immunological synapse in T-cells [ 11 ]. Here, we investigated the role of Rab46 in regulating mast cell degranulation and in establishing the pro-inflammatory environment typical of many immune-related diseases.…”

Section: Introductionmentioning

confidence: 99%

Rab46: a novel player in mast cell function

Pedicini,

Smith,

Savic

et al. 2023

Discovery Immunology

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Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involves selective and agonist-specific release of these active mediators. Whilst a filtering mechanism at the plasma membrane could regulate selective release of some cargo, the plethora of stored cargo and the diversity of mast cell functions suggests the existence of granule subtypes with distinct trafficking pathways. The molecular mechanisms underlying differential trafficking and exocytosis of these granules are not known, neither is it clear how granule trafficking is coupled to the stimulus. In endothelial cells, a Rab GTPase, Rab46, responds to histamine but not thrombin signals, and this regulates the trafficking of a subpopulation of endothelial-specific granules. Here, we sought to explore, for the first time, if Rab46 plays a role in mast cell function. We demonstrate, that Rab46 is highly expressed in human and murine mast cells and Rab46 genetic deletion has an effect on mast cell degranulation that depends on both stimuli and mast cell subtype. This initial insight into the contribution of Rab46 to mast cell function, and the understanding of the role of Rab46 in stimuli-dependent trafficking in other cell types, necessitates further investigations of Rab46 in mast cell granular trafficking so that novel and specific therapeutic targets for treatment of the diverse pathologies mediated by mast cells can be developed.

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Affinity-based proteomics reveals novel binding partners for Rab46 in endothelial cells

Cited by 8 publications

References 41 publications

Proximity labelling identifies pro-migratory endocytic recycling cargo and machinery of the Rab4 and Rab11 families

Proximity labelling identifies pro-migratory endocytic recycling cargo and machinery of the Rab4 and Rab11 families

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Rab46: a novel player in mast cell function

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