The emerging role of retromer in neuroprotection

McMillan, Kirsty J; Korswagen, Hendrick C; Cullen, Peter J.

doi:10.1016/j.ceb.2017.02.004

Cited by 57 publications

(63 citation statements)

References 87 publications

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“…Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.have been linked with a variety of human diseases including Alzheimer's disease, Parkinson's disease, cancer, and diabetes [4,5].Key protein machineries important for the sequence-dependent recycling include the evolutionarily conserved retromer complex (vacuolar protein sorting 35 [VPS35]/VPS26/VPS29 in higher eukaryotes) [6][7][8], the recently discovered retriever [9], the WASH complex [10][11][12], and members of the Sorting Nexin family (SNX) [13][14][15]. A subset of SNX proteins possessing a Bin/Amphiphysin/Rvs (BAR) domain, in addition to the phox-homology (PX) domain, have been linked with the retromer complex.…”

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confidence: 58%

Mechanism of cargo recognition by retromer-linked SNX-BAR proteins

et al. 2020

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Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.have been linked with a variety of human diseases including Alzheimer's disease, Parkinson's disease, cancer, and diabetes [4,5].Key protein machineries important for the sequence-dependent recycling include the evolutionarily conserved retromer complex (vacuolar protein sorting 35 [VPS35]/VPS26/VPS29 in higher eukaryotes) [6][7][8], the recently discovered retriever [9], the WASH complex [10][11][12], and members of the Sorting Nexin family (SNX) [13][14][15]. A subset of SNX proteins possessing a Bin/Amphiphysin/Rvs (BAR) domain, in addition to the phox-homology (PX) domain, have been linked with the retromer complex. The retromer-related SNX-BAR proteins (referred as SNX-BARs herein) SNX1, SNX2, SNX5, SNX6, and SNX32 form heterodimeric complexes and are critical for both endosome-to-plasma membrane recycling and endosome-to-TGN retrieval [16,17]. Current models suggest that SNX-BARs promote the endosome-to-plasma membrane recycling via associating with SNX27 and retromer, with the PDZ domain of SNX27 as the predominant cargo-recognition module [14]. For endosome-to-TGN trafficking, one of the best-characterized cargoes is cation-independent mannose 6-phosphate receptor (CI-MPR), which is necessary to deliver newly synthesized lysosomal hydrolases to the endosomal lumen and thus critical for lysosomal function [18]. However, previous studies have provided contradictory models regarding the role of retromer and SNX-BARs in the endosome-to-TGN retrieval of CI-MPR. Work from many different labs has initially supported the idea that retromer is necessary for the retrieval of CI-MPR, likely through a direct association with its cytoplasmic tail, in particular, the hydrophobic WLM motif [19][20][21]. However, recent work by Cullen and Steinberg has provi...

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confidence: 58%

Mechanism of cargo recognition by retromer-linked SNX-BAR proteins

et al. 2020

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“… since endosomal proteins can be targeted to both the plasma membrane and the TGN, how are specific trafficking routes selected? why do viral and bacterial pathogens target endosomal trafficking pathways? Undoubtedly, answers to these questions will lead us to a better understanding of endosomal receptor trafficking and their functions in organismal development and human disease.…”

Section: Discussionmentioning

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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“…With TFEB playing a central role in adaptive responses to a variety of other cellular stresses (Napolitano and Ballabio, 2016), the synchronized transcriptional control of retromer expression, and hence cargo retrieval and recycling through the endosomal network, is likely to be an important process in the long-term adaptation of cells to these stresses. Finally, with clinical studies having revealed perturbed retromer function in age-related Alzheimer's and Parkinson's diseases (Small and Petsko, 2015;McMillan et al, 2017), the identification of a TFEB-retromer pathway may offer an unexplored strategy through which to enhance retromer expression and thereby increase its neuroprotective role in these and other neurological diseases.…”

Section: Tfeb and Tfe3 Regulate Retromer Expression Upon Nutrient Depmentioning

confidence: 99%

“…While it is clear that hundreds of diverse cargo proteins transit through these dynamic retrieval subdomains en route to the cell surface and the TGN (Burd and Cullen, 2014), how retromer function is regulated and how this impacts the function of the retrieval subdomain remains unclear. What is evident is that disruption of retrieval subdomain function, either through mutations and/or reduced expression of retromer and retromer accessory proteins, is associated with the pathoetiology of a number of neurological disorders that include Alzheimer's and Parkinson's diseases (Small and Petsko, 2015;McMillan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

TFEB controls retromer expression in response to nutrient availability

Curnock

Calcagnì

Ballabio

et al. 2019

Journal of Cell Biology

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Endosomal recycling maintains the cell surface abundance of nutrient transporters for nutrient uptake, but how the cell integrates nutrient availability with recycling is less well understood. Here, in studying the recycling of human glutamine transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), SNAT1 (SLC38A1), and SNAT2 (SLC38A2), we establish that following amino acid restriction, the adaptive delivery of SNAT2 to the cell surface relies on retromer, a master conductor of endosomal recycling. Upon complete amino acid starvation or selective glutamine depletion, we establish that retromer expression is upregulated by transcription factor EB (TFEB) and other members of the MiTF/TFE family of transcription factors through association with CLEAR elements in the promoters of the retromer genes VPS35 and VPS26A. TFEB regulation of retromer expression therefore supports adaptive nutrient acquisition through endosomal recycling.

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The emerging role of retromer in neuroprotection

Abstract: HighlightsIn the endosomal network retromer retrieves cargo away from the degradative pathway.Retromer dysfunction has been implicated in Parkinson’s disease through different mechanisms.These include changes in protein association, protein degradation and mitochondria quality control.

Cited by 57 publications

References 87 publications

Mechanism of cargo recognition by retromer-linked SNX-BAR proteins

Mechanism of cargo recognition by retromer-linked SNX-BAR proteins

Endosomal receptor trafficking: Retromer and beyond

TFEB controls retromer expression in response to nutrient availability

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