Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry

Beer, Katharina; Rivas-Castillo, Jennifer; Kuhn, Kenneth; Fazeli, Gholamreza; Karmann, Birgit; Nance, Jeremy; Stigloher, Christian; Wehman, Ann M.

doi:10.1073/pnas.1714085115

Cited by 65 publications

(75 citation statements)

References 53 publications

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“…Rab9A: Rab9A is a relative of Rab7 that emerged early in metazoan evolution and also acts on endosomes. The top WD scores with the GTP form of Rab9A include several proteins known to act on endosomes including the scaffold protein GRIPAP1/GRASP-1; the HPS3 subunit of the BLOC-2 complex that regulates endosomal traffic; the sorting nexin Snx13 and its paralog Snx14; and the monooxygenase MICALL1 (Gautam et al, 2004;Zheng et al, 2006;Beer et al, 2018;Hoogenraad et al, 2010;Sharma et al, 2009) ( Figure 4D). Other hits included the known Rab9 effector GCC2/golgin-185 and the dynein regulator NDE1/NudE, which was reported as a hit with Rab9 in a yeast two-hybrid screen but did not show nucleotide-specific binding by co-precipitation with Rab9B (Bradshaw and Hayashi, 2017).…”

Section: Application Of Mitoid To a Panel Of Rab Gtpasesmentioning

confidence: 99%

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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The GTPases of the Ras superfamily regulate cell growth, membrane traffic and the cytoskeleton, and a wide range of diseases are caused by mutations in particular members. They function as switchable landmarks with the active GTP-bound form recruiting to the membrane a specific set of effector proteins. The GTPases are precisely controlled by regulators that promote acquisition of GTP (GEFs) or its hydrolysis to GDP (GAPs). We report here MitoID, a method for identifying effectors and regulators by performing in vivo proximity biotinylation with mitochondriallylocalized forms of the GTPases. Applying this to 11 human Rab GTPases identified many known effectors and GAPs, as well as putative novel effectors, with examples of the latter validated for Rab2, Rab5 and Rab9. MitoID can also efficiently identify effectors and GAPs of Rho and Ras family GTPases such as Cdc42, RhoA, Rheb, and N-Ras, and can identify GEFs by use of GDP-bound forms.

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Section: Application Of Mitoid To a Panel Of Rab Gtpasesmentioning

confidence: 99%

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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“…These data suggest that, while the exocyst may play a partial role in the function of RAB-6.2 in the skin, the mechanisms of action of RAB-6.2 likely include additional mechanisms. We also show that extracellular vesicles that are increased by a tat-5 mutation (Beer et al, 2018;Wehman et al, 2011) do not affect cuticle integrity (Fig. S1C).…”

Section: Rab-62 Is Necessary For M Nematophilum Infectionmentioning

confidence: 55%

A conserved retromer-independent function for RAB-6.2/RAB6 inC. elegansepidermis integrity

Kim

Chun

Mangan

et al. 2019

Journal of Cell Science

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Rab proteins are conserved small GTPases that coordinate intracellular trafficking essential to cellular function and homeostasis. RAB-6.2 is a highly conserved C. elegans ortholog of human RAB6 proteins. RAB-6.2 is expressed in most tissues in C. elegans and is known to function in neurons and in the intestine to mediate retrograde trafficking. Here, we show that RAB-6.2 is necessary for cuticle integrity and impermeability in C. elegans. RAB-6.2 functions in the epidermis to instruct skin integrity. Significantly, we show that expression of a mouse RAB6A cDNA can rescue defects in C. elegans epidermis caused by lack of RAB-6.2, suggesting functional conservation across phyla. We also show that the novel function of RAB-6.2 in C. elegans cuticle development is distinct from its previously described function in neurons. Exocyst mutants partially phenocopy rab-6.2-null animals, and rab-6.2-null animals phenocopy mutants that have defective surface glycosylation. These results suggest that RAB-6.2 may mediate the trafficking of one or many secreted glycosylated cuticle proteins directly, or might act indirectly by trafficking glycosylation enzymes to their correct intracellular localization.

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“…show that retrograde trafficking of TAT‐5 is dependent on class III PI3K, RME‐8, and sorting nexin pathways and required to retain PE on the inner leaflet of the plasma membrane. They also demonstrate Dopey homolog PAD‐1 and GEF‐like protein MON‐2 are required for TAT‐5 activity, suggesting they are also regulators of PE asymmetry and EV biogenesis . Although PE externalization correlates strongly with increased MV biogenesis and that its conical shape contributes to membrane curvature, the precise pathway is still unclear.…”

Section: Proteins Regulating MV Biogenesismentioning

confidence: 99%

Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

Taylor

Bebawy

2019

Proteomics

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Microvesicles (MV) are emerging as important mediators of intercellular communication. While MVs are important signaling vectors for many physiological processes, they are also implicated in cancer pathology and progression. Cellular activation is perhaps the most widely reported initiator of MV biogenesis, however, the precise mechanism remains undefined. Uncovering the proteins involved in regulating MV biogenesis is of interest given their role in the dissemination of deleterious cancer traits. MVs shed from drug‐resistant cancer cells transfer multidrug resistance (MDR) proteins to drug‐sensitive cells and confer the MDR phenotype in a matter of hours. MDR is attributed to the overexpression of ABC transporters, primarily P‐glycoprotein and MRP1. Their expression and functionality is dependent on a number of proteins. In particular, FERM domain proteins have been implicated in supporting the functionality of efflux transporters in drug‐resistant cells and in recipient cells during intercellular transfer by vesicles. Herein, the most recent research on the proteins involved in MV biogenesis and in the dissemination of MV‐mediated MDR are discussed. Attention is drawn to unanswered questions in the literature that may prove to be of benefit in ongoing efforts to improve clinical response to chemotherapy and circumventing MDR.

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Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry

Cited by 65 publications

References 53 publications

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

A conserved retromer-independent function for RAB-6.2/RAB6 inC. elegansepidermis integrity

Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

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