SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane.
Postsynaptic density 95/discs large/zonus occludens-1 (PDZ) domain-interacting motifs, in addition to their well-established roles in protein scaffolding at the cell surface, are proposed to act as cis-acting determinants directing the molecular sorting of transmembrane cargo from endosomes to the plasma membrane. This hypothesis requires the existence of a specific trans-acting PDZ protein that mediates the proposed sorting operation in the endosome membrane. Here, we show that sorting nexin 27 (SNX27) is required for efficient PDZ-directed recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes. SNX27 mediates this sorting function when expressed at endogenous levels, and its recycling activity requires both PDZ domain-dependent recognition of the beta(2)AR cytoplasmic tail and Phox homology (PX) domain-dependent association with the endosome membrane. These results identify a discrete role of SNX27 in PDZ-directed recycling of a physiologically important signaling receptor, and extend the concept of cargo-specific molecular sorting in the recycling pathway.
Lauffer
Benjamin E L
BE
Program in Pharmaceutical Sciences and Pharmacogenomics, University of California-San Francisco, San Francisco, CA 94158, USA.
Melero
Cristina
C
Temkin
Paul
P
Lei
Cai
C
Hong
Wanjin
W
Kortemme
Tanja
T
von Zastrow
Mark
M
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D054731:PDZ Domains; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
D010750:Phosphoproteins; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; C522885:SNX27 protein, human; D017923:Sodium-Hydrogen Exchangers; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; C093376:sodium-hydrogen exchanger regulatory factor