A mechanism for retromer endosomal coat complex assembly with cargo

Harrison, Megan S.; Hung, Chih Ming; Liu, Tingting; Christiano, Romain; Walther, Tobias C.; Burd, Christopher G.

doi:10.1073/pnas.1316482111

Cited by 132 publications

(182 citation statements)

References 33 publications

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“…However, it remains to be determined whether GMFG-mediated recycling of ␤1-integrin occurs in cooperation with other components of the trafficking machinery (e.g. SNX17, Ras small GTPase, or Arf6) or promotes recycling of other ␤-integrins to the cell surface membrane (61,62). Therefore, further detailed investigation is needed to determine how GMFG functions in ␤1-integrin recycling.…”

Section: Discussionmentioning

confidence: 99%

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin

Aerbajinai

Liu

Zhu

et al. 2016

Journal of Biological Chemistry

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Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-␥ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and ␤1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1␣ (SDF-1␣) as well as decreased ␣5␤1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of ␣5␤1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of ␤1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of ␤1-integrin back to the plasma membrane following normal endocytosis of ␣5␤1-integrin, suggesting that the involvement of GMFG in maintaining ␣5␤1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting ␤1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxinbinding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased ␤1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited ␤1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of ␣5␤1-integrin and facilitating effective ␤1-integrin recycling back to the plasma membrane.The migration of monocytes from the circulation toward the surrounding extravascular space is a crucial event in physiological and pathological immune and inflammatory responses. The extravasation of monocytes is a highly orchestrated multistep adhesion cascade that is mediated by dynamic regulation of adhesion molecules expressed on both monocytes and endothelial cells, including integrins (1, 2). Integrins are a large family of heterodimeric transmembrane proteins consisting of an ␣-and ␤-subunit that bind extracellular matrix components to provide sites of adhesion and signals for the dynamic rearrangement of cytoskeletal elements in various stages of cell migration (3, 4). Monocytes, like other leukocytes, express distinct integrins, but those most relevant to monocyte migration belong to the ␤1-and ␤2-integrin subfamilies. Although the important role of ␤1/␤2-integrins in regulating monocyte transmigration across the endothelium to sites of inflammation has been relatively well studied (5-7), the molecular mechanisms underpinning the dynamic regulation of endo-exocyt...

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Section: Discussionmentioning

confidence: 99%

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin

Aerbajinai

Liu

Zhu

et al. 2016

Journal of Biological Chemistry

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“…The Vps26-Vps29-Vps35 trimer is in turn responsible for cargo recruitment by binding the cytosolic tail of transmembrane receptors (Arighi et al, 2004;Mukadam and Seaman, 2015). Recently, it has been demonstrated that Vps35 recruits retromer to membrane by recognizing SNX3 and Rab7a (Harrison et al, 2014). The key role of Vps35 in retromer recruitment is further supported by the evidence that mutations in the VPS35 gene are associated with neurodegenerative diseases, such as Alzheimer's or Parkinson's (see Table 1).…”

Section: Endosomal Carrier Formationmentioning

confidence: 94%

Bidirectional traffic between the Golgi and the endosomes – machineries and regulation

Progida

Bakke

2016

Journal of Cell Science

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The bidirectional transport between the Golgi complex and the endocytic pathway has to be finely regulated in order to ensure the proper delivery of newly synthetized lysosomal enzymes and the return of sorting receptors from degradative compartments. The high complexity of these routes has led to experimental difficulties in properly dissecting and separating the different pathways. As a consequence, several models have been proposed during the past decades. However, recent advances in our understanding of endosomal dynamics have helped to unify these different views. We provide here an overview of the current insights into the transport routes between Golgi and endosomes in mammalian cells. The focus of the Commentary is on the key molecules involved in the trafficking pathways between these intracellular compartments, such as Rab proteins and sorting receptors, and their regulation. A proper understanding of the bidirectional traffic between the Golgi complex and the endolysosomal system is of uttermost importance, as several studies have demonstrated that mutations in the factors involved in these transport pathways result in various pathologies, in particular lysosome-associated diseases and diverse neurological disorders, such as Alzheimer's and Parkinson's disease.

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“…However, it is the combination of the small GTPase Rab7a and phox homology (PX)-containing protein SNX3 that is thought to initiate this cascade by recruiting retromer to the membrane (24,40). The current view of retromer mediated transport is P316S, or Vps35 R524W-GFP (error bars, S.E.…”

Section: Vps35 R524w Mutation Impairs the Function Of Retromermentioning

confidence: 99%

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Follett

Bugarčić

Yang

et al. 2016

Journal of Biological Chemistry

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Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting. Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular ␣-synuclein-positive aggregates, a hallmark of Parkinson disease. Overall, the Vps35 R524W-containing retromer has a decreased endosomal association, which can be partially rescued by R55, a small molecule previously shown to stabilize the retromer complex, supporting the potential for future targeting of the retromer complex in the treatment of Parkinson disease.

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A mechanism for retromer endosomal coat complex assembly with cargo

Cited by 132 publications

References 33 publications

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin

Bidirectional traffic between the Golgi and the endosomes – machineries and regulation

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

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