Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles

Nag, Sudeshna; Rani, Shikha; Mahanty, Sarmistha; Bissig, Christin; Arora, Pooja; Azevedo, Cristina; Saiardi, Adolfo; Sluijs, Peter van der; Delevoye, Cédric; Niel, Guillaume van; Raposo, Graça; Setty, Subba Rao Gangi

doi:10.1242/jcs.216226

Cited by 26 publications

(22 citation statements)

References 73 publications

(138 reference statements)

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“…Herein, we have demonstrated that Rab4A is a modulator of endocytic volume because Rab4A overexpression leads to increased endosomal size in both MCF10A and MDA-MB-231, whereas knockdown of Rab4A results in increased endosomal size in MCF10A but not in MDA-MB-231 cells. Previously, similar results have been shown in other cell types (59)(60)(61), suggesting that precise control of Rab4 expression regulates EE volume in a cell-specific manner. Considering that Rab4 has been shown to be involved in both membrane fusion and fission events (58,62), changes in Rab4 expression could result in increased EE size.…”

Section: Discussionsupporting

confidence: 83%

Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation

Tubbesing

Ward

Abini-Agbomson

et al. 2020

Molecular Cancer Research

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Early sorting endosomes are responsible for the trafficking and function of transferrin receptor (TfR) and EGFR. These receptors play important roles in iron uptake and signaling and are critical for breast cancer development. However, the role of morphology, receptor composition, and signaling of early endosomes in breast cancer remains poorly understood. A novel population of enlarged early endosomes was identified in breast cancer cells and tumor xenografts but not in noncancerous MCF10A cells. Quantitative analysis of endosomal morphology, cargo sorting, EGFR activation, and Rab GTPase regulation was performed using superresolution and confocal microscopy followed by 3D rendering. MDA-MB-231 breast cancer cells have fewer, but larger EEA1positive early endosomes compared with MCF10A cells. Live-cell imaging indicated dysregulated cargo sorting, because EGF and Tf traffic together via enlarged endosomes in MDA-MB-231, but not in MCF10A. Large EEA1-positive MDA-MB-231 endosomes exhibited prolonged and increased EGF-induced activation of EGFR upon phosphorylation at tyrosine-1068 (EGFR-p1068). Rab4A overexpression in MCF10A cells produced EEA1-positive enlarged endosomes that displayed prolonged and amplified EGF-induced EGFR-p1068 activation. Knockdown of Rab4A lead to increased endosomal size in MCF10A, but not in MDA-MB-231 cells. Nevertheless, Rab4A knockdown resulted in enhanced EGF-induced activation of EGFR-p1068 in MDA-MB-231 as well as downstream signaling in MCF10A cells. Altogether, this extensive characterization of early endosomes in breast cancer cells has identified a Rab4-modulated enlarged early endosomal compartment as the site of prolonged and increased EGFR activation.Implications: Enlarged early endosomes play a Rab4-modulated role in regulation of EGFR activation in breast cancer cells.

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Section: Discussionsupporting

confidence: 83%

Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation

Tubbesing

Ward

Abini-Agbomson

et al. 2020

Molecular Cancer Research

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“…Rab7 regulates formation of the late endosome, from which retromer, retriever and COMMD/CCDC22/CCDC93 (CCC)dependent cargo retrieval and recycling occurs (McNally et al, 2017;Purushothaman et al, 2017;Singla et al, 2019) or from which cargoes are directed to the lysosome for degradation (Guerra and Bucci, 2016). Rab4 is predominantly localized to the Rab5 + sorting endosomal compartment (Sönnichsen et al, 2000) and can regulate cargo transfer into both Rab11 recycling and cellular degradative pathways (McCaffrey et al, 2001;Nag et al, 2018). Little is known about the composition of membranes that recruit Rab4, however.…”

Section: Endosomal Sortingmentioning

confidence: 99%

Membrane Heterogeneity Controls Cellular Endocytic Trafficking

Redpath

Betzler

Rossatti

et al. 2020

Front. Cell Dev. Biol.

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Endocytic trafficking relies on highly localized events in cell membranes. Endocytosis involves the gathering of protein (cargo/receptor) at distinct plasma membrane locations defined by specific lipid and protein compositions. Simultaneously, the molecular machinery that drives invagination and eventually scission of the endocytic vesicle assembles at the very same place on the inner leaflet of the membrane. It is membrane heterogeneity-the existence of specific lipid and protein domains in localized regions of membranes-that creates the distinct molecular identity required for an endocytic event to occur precisely when and where it is required rather than at some random location within the plasma membrane. Accumulating evidence leads us to believe that the trafficking fate of internalized proteins is sealed following endocytosis, as this distinct membrane identity is preserved through the endocytic pathway, upon fusion of endocytic vesicles with early and sorting endosomes. In fact, just like at the plasma membrane, multiple domains coexist at the surface of these endosomes, regulating local membrane tubulation, fission and sorting to recycling pathways or to the trans-Golgi network via late endosomes. From here, membrane heterogeneity ensures that fusion events between intracellular vesicles and larger compartments are spatially regulated to promote the transport of cargoes to their intracellular destination.

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“…For example, Rab6A and its effector ELKS regulate the transport of Dct from the trans ‐Golgi network (TGN) to melanosomes, and Rab6A‐melanocyte‐specific conditional KO mice exhibit hypopigmentation (Patwardhan et al., 2017). Rab4A and its two effectors are involved in the sorting of melanogenic enzymes on early endosomes (Nag et al., 2018), and Rab22A is involved in the biogenesis of tubular recycling endosomes through recruitment of BLOC‐1 and BLOC‐2, both of which are required for melanogenic enzyme transport (Shakya et al., 2018). Rab9A, which is present on early/recycling endosomes and melanosomes in melanocytes, also plays a role in delivery of melanosomal cargos (e.g., Tyr and Tyrp1) from syntaxin‐13‐positive recycling endosomes to melanosomes (Mahanty et al., 2016; Marubashi, et al., 2016).…”

Section: Rab Gtpases In Melanosome Biogenesis In Melanocytesmentioning

confidence: 99%

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

Fukuda

2020

Pigment Cell Melanoma Res

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Melanosomes are specialized intracellular organelles that produce and store melanin pigments in melanocytes, which are present in several mammalian tissues and organs, including the skin, hair, and eyes. Melanosomes form and mature stepwise (stages I–IV) in melanocytes and then are transported toward the plasma membrane along the cytoskeleton. They are subsequently transferred to neighboring keratinocytes by a largely unknown mechanism, and incorporated melanosomes are transported to the perinuclear region of the keratinocytes where they form melanin caps. Melanocytes also extend several dendrites that facilitate the efficient transfer of the melanosomes to the keratinocytes. Since the melanosome biogenesis, transport, and transfer steps require multiple membrane trafficking processes, Rab GTPases that are conserved key regulators of membrane traffic in all eukaryotes are crucial for skin and hair pigmentation. Dysfunctions of two Rab isoforms, Rab27A and Rab38, are known to cause a hypopigmentation phenotype in human type 2 Griscelli syndrome patients and in chocolate mice (related to Hermansky–Pudlak syndrome), respectively. In this review article, I review the literature on the functions of each Rab isoform and its upstream and downstream regulators in mammalian melanocytes and keratinocytes.

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Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles

Cited by 26 publications

References 73 publications

Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation

Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation

Membrane Heterogeneity Controls Cellular Endocytic Trafficking

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

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