The Retromer Complex Influences Wnt Secretion by Recycling Wntless from Endosomes to the Trans-Golgi Network

The highly conserved retromer complex has been linked to cargo retrieval from endosomes to the trans-Golgi network. In this issue, Kvainickas et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702137) and Simonetti et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703015) fundamentally question the current retromer model and demonstrate that in mammalian cells, the individual retromer subcomplexes have functionally diverged to organize multiple distinct sorting pathways.

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Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner

Journal of Cell Science ◽

10.1242/jcs.246819 ◽

2020 ◽

Vol 133 (24) ◽

pp. jcs246819 ◽

Cited By ~ 1

Author(s):

Santanu Das ◽

Saptarshi Maji ◽

Ruturaj ◽

Indira Bhattacharya ◽

Tanusree Saha ◽

...

Keyword(s):

Wilson Disease ◽

Dependent Manner ◽

Copper Transporter ◽

Copper Chelation ◽

Trans Golgi Network ◽

Wilson Disease Protein ◽

Retromer Complex ◽

High Copper ◽

Disease Protein ◽

Golgi Network

ABSTRACTThe Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.

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Cargo-selective SNX-BAR proteins mediate retromer trimer independent retrograde transport

The Journal of Cell Biology ◽

10.1083/jcb.201702137 ◽

2017 ◽

Vol 216 (11) ◽

pp. 3677-3693 ◽

Cited By ~ 60

Author(s):

Arunas Kvainickas ◽

Ana Jimenez-Orgaz ◽

Heike Nägele ◽

Zehan Hu ◽

Jörn Dengjel ◽

...

Keyword(s):

Quantitative Proteomics ◽

Retrograde Transport ◽

Dependent Manner ◽

Sorting Nexin ◽

Trans Golgi Network ◽

The Core ◽

Retromer Complex ◽

Mannose 6 Phosphate ◽

Golgi Network

The retromer complex, which recycles the cation-independent mannose 6-phosphate receptor (CI-MPR) from endosomes to the trans-Golgi network (TGN), is thought to consist of a cargo-selective VPS26–VPS29–VPS35 trimer and a membrane-deforming subunit of sorting nexin (SNX)–Bin, Amphyphysin, and Rvs (BAR; SNX-BAR) proteins. In this study, we demonstrate that heterodimers of the SNX-BAR proteins, SNX1, SNX2, SNX5, and SNX6, are the cargo-selective elements that mediate the retrograde transport of CI-MPR from endosomes to the TGN independently of the core retromer trimer. Using quantitative proteomics, we also identify the IGF1R, among more potential cargo, as another SNX5 and SNX6 binding receptor that recycles through SNX-BAR heterodimers, but not via the retromer trimer, in a ligand- and activation-dependent manner. Overall, our data redefine the mechanics of retromer-based sorting and call into question whether retromer indeed functions as a complex of SNX-BAR proteins and the VPS26–VPS29–VPS35 trimer.

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