SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors

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Abstract
Internalization and endocytic recycling of the β2-adrenergic receptor (β2AR) is critical for its signalling activities and is known to depend on sorting nexin 27 (SNX27). SNX27 is now shown to link β2AR to the retromer complex to mediate recycling of the receptor. Endocytic sorting of signalling receptors between recycling and degradative pathways is a key cellular process controlling the surface complement of receptors and, accordingly, the cell’s ability to respond to specific extracellular stimuli. The β2 adrenergic receptor (β2AR) is a prototypical seven-transmembrane signalling receptor that recycles rapidly and efficiently to the plasma membrane after ligand-induced endocytosis. β2AR recycling is dependent on the receptor’s carboxy-terminal PDZ ligand and Rab4 (refs 1, 2). This active sorting process is required for functional resensitization of β2AR-mediated signalling3,4. Here we show that sequence-directed sorting occurs at the level of entry into retromer tubules and that retromer tubules are associated with Rab4. Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential adaptor protein linking β2ARs to the retromer tubule. SNX27 does not seem to directly interact with the retromer core complex, but does interact with the retromer-associated Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complex. The present results identify a role for retromer in endocytic trafficking of signalling receptors, in regulating a receptor-linked signalling pathway, and in mediating direct endosome-to-plasma membrane traffic.