Abstract
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.
Highlights
Cell surface integral-membrane proteins and their ligands taken up during endocytosis are either sent to lysosome for degradation or subjected to recycling back to the plasma membrane directly or via the trans-Golgi network (TGN) [1,2,3]
The Sorting Nexin family (SNX)-BAR-binding motif (SBM) is distinct from the short motifs recognized by the SNX3-retromer [13], SNX17 [44], and SNX27 [14, 45], suggesting that each subfamily of the SNX proteins play a major role in selecting the cargoes, in addition to contacting phosphoinositides and promoting the formation of tubular structures [46] (Fig 6)
We and others demonstrate that SNX-BARs, SNX27, and retromer are all involved in the endocytic recycling of many transmembrane proteins, such as semaphorin 4C (SEMA4C), Parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR), TRAIL receptor 1 (TRAILR1), and Glucose Transporter Type 1 (GLUT1) [14]
Summary
Cell surface integral-membrane proteins and their ligands taken up during endocytosis are either sent to lysosome for degradation or subjected to recycling back to the plasma membrane directly or via the trans-Golgi network (TGN) [1,2,3]. These processes, known as endosomal protein sorting, are essential to maintain plasma membrane homeostasis and indispensable for proper cellular responses to external signals [1,2,3]. Emphasizing the importance of endosomal protein sorting is the observation that genetic defects in these processes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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