The adaptor protein GULP promotes Jedi-1-mediated phagocytosis through a clathrin-dependent mechanism.

Sullivan CS, Scheib JL, Ma Z, Dang RP, Schafer JM, Hickman FE, Brodsky FM, Ravichandran KS, Carter BD
Mol Biol Cell. 2014 25 (12): 1925-36

PMID: 24743597 · PMCID: PMC4055271 · DOI:10.1091/mbc.E13-11-0658

During the development of the peripheral nervous system, the large number of apoptotic neurons generated are phagocytosed by glial precursor cells. This clearance is mediated, in part, through the mammalian engulfment receptor Jedi-1. However, the mechanisms by which Jedi-1 mediates phagocytosis are poorly understood. Here we demonstrate that Jedi-1 associates with GULP, the mammalian homologue of CED-6, an adaptor protein required for phagocytosis mediated by the nematode engulfment receptor CED-1. Silencing GULP or mutating the NPXY motif in Jedi-1, which is required for GULP binding, prevents Jedi-1-mediated phagocytosis. How GULP promotes engulfment is not known. Of interest, we find that Jedi-1-induced phagocytosis requires GULP binding to clathrin heavy chain (CHC). During engulfment, CHC is tyrosine phosphorylated, which is required for Jedi-mediated engulfment. Both phosphoclathrin and actin accumulate around engulfed microspheres. Furthermore, knockdown of CHC in HeLa cells prevents Jedi-1-mediated engulfment of microspheres, and knockdown in glial precursors prevents the engulfment of apoptotic neurons. Taken together, these results reveal that Jedi-1 signals through recruitment of GULP, which promotes phagocytosis through a noncanonical phosphoclathrin-dependent mechanism.

© 2014 Sullivan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

MeSH Terms (13)

3T3 Cells Actins Adaptor Proteins, Signal Transducing Amino Acid Motifs Animals Clathrin HeLa Cells Humans Membrane Proteins Mice Phagocytosis Protein Interaction Domains and Motifs Protein Transport

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