WLS retrograde transport to the endoplasmic reticulum during Wnt secretion.
Wnts are transported to the cell surface by the integral membrane protein WLS (also known as Wntless, Evi, and GPR177). Previous studies of WLS trafficking have emphasized WLS movement from the Golgi to the plasma membrane (PM) and then back to the Golgi via retromer-mediated endocytic recycling. We find that endogenous WLS binds Wnts in the endoplasmic reticulum (ER), cycles to the PM, and then returns to the ER through the Golgi. We identify an ER-targeting sequence at the carboxyl terminus of native WLS that is critical for ER retrograde recycling and contributes to Wnt secretory function. Golgi-to-ER recycling of WLS requires the COPI regulator ARF as well as ERGIC2, an ER-Golgi intermediate compartment protein that is also required for the retrograde trafficking of the KDEL receptor and certain toxins. ERGIC2 is required for efficient Wnt secretion. ER retrieval is an integral part of the WLS transport cycle.
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Jia
J
Yu
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138673, Singapore.
Joanne
J
Chia
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Claire Ann
CA
Canning
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
C Michael
CM
Jones
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138673, Singapore.
Frédéric A
FA
Bard
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore; Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore; Department of Pediatrics, Duke University, Durham, NC 27710, USA. Electronic address: david.virshup@duke-nus.edu.sg.
David M
DM
Virshup
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism*; D020727:ADP-Ribosylation Factors / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D020755:Coat Protein Complex I; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009865:Oocytes; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism; D022161:Transport Vesicles; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D060509:Wnt3A Protein / Q000378:metabolism*; D014982:Xenopus laevis
D020755:Coat Protein Complex I; C431845:ERGIC2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C064459:KDEL receptor; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D033921:Vesicular Transport Proteins; C549111:WLS protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C116687:ARF3 protein, human; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; C116688:ARF4 protein, human; C116691:ARF5 protein, human