title: Human Diversity in a Cell Surface Receptor that Inhibits Autophagy.
abstract: Mutations in genes encoding autophagy proteins have been associated with human autoimmune diseases, suggesting that diversity in autophagy responses could be associated with disease susceptibility or severity. A cellular genome-wide association study (GWAS) screen was performed to explore normal human diversity in responses to rapamycin, a microbial product that induces autophagy. Cells from several human populations demonstrated variability in expression of a cell surface receptor, CD244 (SlamF4, 2B4), that correlated with changes in rapamycin-induced autophagy. High expression of CD244 and receptor activation with its endogenous ligand CD48 inhibited starvation- and rapamycin-induced autophagy by promoting association of CD244 with the autophagy complex proteins Vps34 and Beclin-1. The association of CD244 with this complex reduced Vps34 lipid kinase activity. Lack of CD244 is associated with auto-antibody production in mice, and lower expression of human CD244 has previously been implicated in severity of human rheumatoid arthritis and systemic lupus erythematosus, indicating that increased autophagy as a result of low levels of CD244 may alter disease outcomes.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Chaudhary
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Leite
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bridget R
authors.initials: BR
authors.lastname: Kulasekara
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Altura
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Ogahara
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Weiss
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Blanc
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Keeffe
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: millersi@uw.edu.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1 / Q000378:metabolism; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071186:Beclin-1; C084093:CD244 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D058546:Class III Phosphatidylinositol 3-Kinases