A bipartite sorting signal ensures specificity of retromer complex in membrane protein recycling

Suzuki, S.; Chuang, Ya-Shan; Li, Ming; Seaman, Matthew N.; Emr, Scott D.

doi:10.1083/jcb.201901019

Cited by 36 publications

(50 citation statements)

References 43 publications

(60 reference statements)

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“…Moreover, a previous study reporting a comparable half-life of sortilin in AP-1 knockout and wild-type cells supports our finding that the phosphorylation of Ser 15 results in a decreased affinity for AP-1 complexes and "missorting" but not in a shorter sortilin half-life (20). Recent findings suggest that retromer binding in yeast is conveyed by a bipartite site in receptor cytoplasmic domains (28). This could evidently also be the case for mammalian receptors such as sortilin.…”

Section: Figsupporting

confidence: 91%

“…In regard to sortilin trafficking, the role of PACS-1 (and, to some extent, that of the GGAs) is still unclear, but several studies have established that AP-2 is involved in the endocytosis of sortilin, whereas the remaining adaptors participate in its Golgiendosome cycling (21,26,27). A single functional site (F 787 LV 789 ), possibly part of an as-yet-unidentified bipartite retromer-binding site, for retromer binding has been reported (26,28), but two of the most important sorting sites in sortilin are particularly well defined. The first, which contributes to Golgi-endosome trafficking (and more modestly to endocytosis) and is made up of a C-terminal acidic cluster combined with a dileucine (D 823 DSDEDLL 830 ), is targeted by PACS-1, AP-1 and -2, as well as the GGA proteins (20,21).…”

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confidence: 99%

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PAK Kinases Target Sortilin and Modulate Its Sorting

Pallesen

Gustafsen

Cramer

et al. 2020

Molecular and Cellular Biology

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The multifunctional type 1 receptor sortilin is involved in endocytosis and intracellular transport of ligands. The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. The C-terminal acidic cluster harbors a serine residue, which is subject to phosphorylation by casein kinase. Phosphorylation of this serine residue is known to modulate adaptor binding to sortilin. Here, we show that the cytoplasmic domain of sortilin also engages Rac-p21-activated kinases 1 to 3 (PAK1-3) via a binding segment that includes a tyrosine-based motif, also encompassing a serine residue. We further demonstrate that PAK1-3 specifically phosphorylate this serine residue and that this phosphorylation alters the affinity for AP-1 binding and consequently changes the intracellular localization of sortilin as a result of modulated trafficking. Our findings suggest that trafficking of ligands bound to sortilin is in part regulated by group A PAK kinases, which are downstream effectors of Rho GTPases and are known to affect a variety of processes by remodeling the cytoskeleton and by promoting gene transcription and cell survival.

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Section: Figsupporting

confidence: 91%

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confidence: 99%

PAK Kinases Target Sortilin and Modulate Its Sorting

Pallesen

Gustafsen

Cramer

et al. 2020

Molecular and Cellular Biology

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“…Interestingly, a recent paper by Emr and colleagues revealed that VPS10, the functional homolog of CI-MPR in yeast, also contains a bipartite signal required for its endosomal retrieval [52]. In contrast with CI-MPR, the bipartite signal of VPS10 is recognized by the retromer subunit VPS35 and VPS26, but not by VPS17, the yeast ortholog of SNX5 and SNX6.…”

Section: Plos Biologymentioning

confidence: 99%

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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“…Multiple distinct cargo-recognizing mechanisms have been discovered. For instance, yeast Vps10 contains a bipartite signal that is recognized by the retromer subunit Vps35 and Vps26 (Suzuki et al, 2019). In mammals, the SNX3-retromer complex mediates the transport of wntless, DMT1 (divalent metal transporter 1), and CI-MPR, via recognizing the aromatic, hydrophobic motif in their cytoplasmic tails (Harterink et al, 2011;Zhang et al, 2011;Harrison et al, 2014;Lucas et al, 2016;Cui et al, 2019).…”

Section: Retromermentioning

confidence: 99%

Endosome-to-TGN Trafficking: Organelle-Vesicle and Organelle-Organelle Interactions

Zhao

Billadeau

et al. 2020

Front. Cell Dev. Biol.

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Retrograde transport from endosomes to the trans-Golgi network (TGN) diverts proteins and lipids away from lysosomal degradation. It is essential for maintaining cellular homeostasis and signaling. In recent years, significant advancements have been made in understanding this classical pathway, revealing new insights into multiple steps of vesicular trafficking as well as critical roles of ER-endosome contacts for endosomal trafficking. In this review, we summarize up-to-date knowledge about this trafficking pathway, in particular, mechanisms of cargo recognition at endosomes and vesicle tethering at the TGN, and contributions of ER-endosome contacts.

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A bipartite sorting signal ensures specificity of retromer complex in membrane protein recycling

Cited by 36 publications

References 43 publications

PAK Kinases Target Sortilin and Modulate Its Sorting

PAK Kinases Target Sortilin and Modulate Its Sorting

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

Endosome-to-TGN Trafficking: Organelle-Vesicle and Organelle-Organelle Interactions

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