Retromer- and WASH-dependent sorting of nutrient transporters requires a multivalent interaction network with ANKRD50

Kvainickas, Arunas; Orgaz, Ana Jimenez; Nägele, Heike; Diedrich, Britta; Heesom, Kate J; Dengjel, Jörn; Cullen, Peter J.; Steinberg, Florian

doi:10.1242/jcs.196758

Cited by 49 publications

(61 citation statements)

References 42 publications

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“…Importantly, SLC3A2 total protein levels were also downregulated in WASH and retromer knockout cells (Fig A and D). This latter finding is also in accordance with previous proteomic studies and argues for a common trafficking pathway essential for both SLC3A2 and Basigin sorting and requiring RAB21, WASH, and the retromer.…”

Section: Resultssupporting

confidence: 92%

APEX2‐mediated RAB proximity labeling identifies a role for RAB21 in clathrin‐independent cargo sorting

et al. 2019

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RAB GTPases are central modulators of membrane trafficking. They are under the dynamic regulation of activating guanine exchange factors (GEFs) and inactivating GTPase‐activating proteins (GAPs). Once activated, RABs recruit a large spectrum of effectors to control trafficking functions of eukaryotic cells. Multiple proteomic studies, using pull‐down or yeast two‐hybrid approaches, have identified a number of RAB interactors. However, due to the in vitro nature of these approaches and inherent limitations of each technique, a comprehensive definition of RAB interactors is still lacking. By comparing quantitative affinity purifications of GFP:RAB21 with APEX2‐mediated proximity labeling of RAB4a, RAB5a, RAB7a, and RAB21, we find that APEX2 proximity labeling allows for the comprehensive identification of RAB regulators and interactors. Importantly, through biochemical and genetic approaches, we establish a novel link between RAB21 and the WASH and retromer complexes, with functional consequences on cargo sorting. Hence, APEX2‐mediated proximity labeling of RAB neighboring proteins represents a new and efficient tool to define RAB functions.

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Section: Resultssupporting

confidence: 92%

APEX2‐mediated RAB proximity labeling identifies a role for RAB21 in clathrin‐independent cargo sorting

et al. 2019

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“…This was further confirmed by our RAB7 knockout and rescue experiments, which established that GTP‐locked RAB7 is fully competent in restoring retromer‐mediated recycling. We have just reported that the retrograde sorting of CI‐MPR does not depend on the retromer trimer; instead, we found even slightly faster delivery of CI‐MPR to the TGN in VPS35‐deficient cells (Kvainickas et al , a,b). It remains to be explored further whether the control of RAB7 activity is a modulating factor for the SNX‐BAR‐dependent transport of CI‐MPR that we observed.…”

Section: Discussionmentioning

confidence: 63%

“…Loss of the retromer‐associated proteins VARP (Hesketh et al , ) and FAM21 (Gomez & Billadeau, ) led to a decrease in lysosomal RAB7, suggesting lower RAB7 activity (Fig A). We could not detect significant changes with the retromer and FAM21 binding proteins ANKRD50 (Kvainickas et al , b) and FKBP15 (Harbour et al , ). The same set of cells was also subjected to the GST‐RILP‐based RAB7 activity assay, which confirmed the results from the microscopy‐based screen, as loss of TBC1D5 and to a lesser extent SNX1/2 and VAMP7 led to an increase in RILP‐bound, active RAB7, whereas loss of FAM21 and VARP resulted in less active RAB7 that bound to the beads (Fig B).…”

Section: Resultsmentioning

confidence: 71%

Control of RAB 7 activity and localization through the retromer‐TBC1D5 complex enables RAB 7‐dependent mitophagy

Jimenez-Orgaz¹,

Kvainickas²,

Nägele³

et al. 2017

The EMBO Journal

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Retromer is an endosomal multi‐protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans‐Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer‐associated RAB7‐specific GAP TBC1D5. In the absence of either TBC1D5 or retromer, RAB7 activity state and localization are no longer controlled and hyperactivated RAB7 expands over the entire lysosomal domain. This lysosomal accumulation of hyperactivated RAB7 results in a striking loss of RAB7 mobility and overall depletion of the inactive RAB7 pool on endomembranes. Functionally, we establish that this control of RAB7 activity is not required for the recycling of retromer‐dependent cargoes, but instead enables the correct sorting of the autophagy related transmembrane protein ATG9a and autophagosome formation around damaged mitochondria during Parkin‐mediated mitophagy.

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“…FAM21 is comprised of a head domain (~220 amino acids), which is necessary to interact with other members of the WASH complex, and an extended C‐terminal tail containing 21 repeats of a novel acidic motif (L‐F‐[D/E] 3‐10 ‐L‐F), termed the LFa motif. The FAM21 tail has been suggested to function as an endosomal signaling hub recruiting numerous proteins, including the actin‐capping protein CapZ, ANKRD50, FKBP15, TBC1d23, RME‐8 and the CCC complex (Figure A).…”

Section: Wash Complexmentioning

confidence: 99%

Endosomal receptor trafficking: Retromer and beyond

Wang

Fedoseienko

Chen

et al. 2018

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The tubular endolysosomal network is a quality control system that ensures the proper delivery of internalized receptors to specific subcellular destinations in order to maintain cellular homeostasis. Although retromer was originally described in yeast as a regulator of endosome-to-Golgi receptor recycling, mammalian retromer has emerged as a central player in endosome-to-plasma membrane recycling of a variety of receptors. Over the past decade, information regarding the mechanism by which retromer facilitates receptor trafficking has emerged, as has the identification of numerous retromer-associated molecules including the WASH complex, sorting nexins (SNXs) and TBC1d5. Moreover, the recent demonstration that several SNXs can directly interact with retromer cargo to facilitate endosome-to-Golgi retrieval has provided new insight into how these receptors are trafficked in cells. The mechanism by which SNX17 cargoes are recycled out of the endosomal system was demonstrated to involve a retromer-like complex termed the retriever, which is recruited to WASH positive endosomes through an interaction with the COMMD/CCDC22/CCDC93 (CCC) complex. Lastly, the mechanisms by which bacterial and viral pathogens highjack this complex sorting machinery in order to escape the endolysosomal system or remain hidden within the cells are beginning to emerge. In this review, we will highlight recent studies that have begun to unravel the intricacies by which the retromer and associated molecules contribute to receptor trafficking and how deregulation at this sorting domain can contribute to disease or facilitate pathogen infection.

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Retromer- and WASH-dependent sorting of nutrient transporters requires a multivalent interaction network with ANKRD50

Cited by 49 publications

References 42 publications

APEX2‐mediated RAB proximity labeling identifies a role for RAB21 in clathrin‐independent cargo sorting

APEX2‐mediated RAB proximity labeling identifies a role for RAB21 in clathrin‐independent cargo sorting

Control of RAB 7 activity and localization through the retromer‐TBC1D5 complex enables RAB 7‐dependent mitophagy

Endosomal receptor trafficking: Retromer and beyond

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