Snx3 Regulates Recycling of the Transferrin Receptor and Iron Assimilation

Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi; Seguin, Alexandra; Li, Liangtao; Fegan, Katherine H.; Hildick-Smith, Gordon J.; Shah, Dhvanit I.; Cooney, James; Chen, Wen; King, Michael; Yien, Yvette Y.; Schultz, Iman J.; Anderson, Heidi; Dalton, Abigail Goodnow; Freedman, Matthew L.; Kingsley, Paul D.; Palis, James; Hattangadi, Shilpa M.; Lodish, Harvey F.; Ward, Daniel Alexander; Kaplan, Jerry; Maeda, Takahiro; Ponka, Prem; Paw, Barry H.

doi:10.1016/j.cmet.2013.01.013

Cited by 107 publications

(114 citation statements)

References 55 publications

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“…However, a formal test of this hypothesis is lacking. Retromer binds sorting nexin 3 [henceforth referred to as SNX3 (human) or Snx3 (yeast)] (12)(13)(14)(15), and in SNX3 knockdown cells, less retromer is associated with endosomes (14). In this study, we show that SNX3 and RAB7 are coordinately recognized by retromer and that these interactions are sufficient to recruit retromer to a membrane where they poise retromer to capture integral membrane retrograde cargo.…”

mentioning

confidence: 69%

A mechanism for retromer endosomal coat complex assembly with cargo

Harrison

Hung

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

145

172

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Retromer is an evolutionarily conserved protein complex composed of the VPS26, VPS29, and VPS35 proteins that selects and packages cargo proteins into transport carriers that export cargo from the endosome. The mechanisms by which retromer is recruited to the endosome and captures cargo are unknown. We show that membrane recruitment of retromer is mediated by bivalent recognition of an effector of PI3K, SNX3, and the RAB7A GTPase, by the VPS35 retromer subunit. These bivalent interactions prime retromer to capture integral membrane cargo, which enhances membrane association of retromer and initiates cargo sorting. The role of RAB7A is severely impaired by a mutation, K157N, that causes Charcot-Marie-Tooth neuropathy 2B. The results elucidate minimal requirements for retromer assembly on the endosome membrane and reveal how PI3K and RAB signaling are coupled to initiate retromer-mediated cargo export.sorting nexin | mass spectrometry | biochemical reconstitution | proteoliposome

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mentioning

confidence: 69%

A mechanism for retromer endosomal coat complex assembly with cargo

Harrison

Hung

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

145

172

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“…Interestingly, SNCA and DNAJC13, mutated in patients with PD, modulate TFR1 trafficking (72)(73)(74). VPS35, another PD disease gene, helps sort TFR1 to recycling endosomes, and insufficiency of its retromer complex causes cellular iron deficiency (75). RAB5B, which interacts with PD protein LRRK2, is also involved in endosomal trafficking of TFR1 (76,77).…”

Section: Resultsmentioning

confidence: 99%

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Matak

Moustafa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.iron | transferrin receptor | ferroportin | dopaminergic neuron | neurodegeneration

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“…Collectively, these studies indicate a critical role for maternal iron status and dietary iron in early neural development. These data may also explain the requirement for a high level of Sorting Nexin 3 (Snx3), Mitoferrin 1 (Mfrn1, Slc25a37), and -2 (Mfrn2, Slc25a28) expression, required for iron import, in vertebrate neural tissues (25)(26)(27).…”

mentioning

confidence: 99%