title: TIM family proteins promote the lysosomal degradation of the nuclear receptor NUR77.
abstract: T cell immunoglobulin and mucin domain (TIM) proteins are cell-surface signaling receptors in T cells and scavenger receptors in antigen-presenting cells and kidney tubular epithelia. Here, we demonstrated a function for TIM proteins in mediating the degradation of NUR77, a nuclear receptor implicated in apoptosis and cell survival. TIM proteins interacted with and mediated the lysosomal degradation of NUR77 in a phosphoinositide 3-kinase-dependent pathway. We also showed dynamic cycling of TIM-1 to and from the cell surface through clathrin-dependent constitutive endocytosis. Blocking this process or mutating the phosphatidylserine-binding pocket in TIM-1 abrogated TIM-1-mediated degradation of NUR77. In an in vitro model of kidney injury, silencing TIM-1 increased NUR77 abundance and decreased epithelial cell survival. These results show that TIM proteins may affect immune cell function and the response of the kidney to injury.
authors.affiliation: Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. skota@bidmc.harvard.edu
authors.forename: Savithri
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Satya Keerthi
authors.initials: SK
authors.lastname: Kota
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004705:Endocytosis / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006367:HeLa Cells; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007668:Kidney / Q000166:cytology; D008156:Luciferases; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D011991:Receptors, Virus / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D017931:DNA Primers; D000072596:Hepatitis A Virus Cellular Receptor 1; D008156:Luciferases; D008562:Membrane Glycoproteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019869:Phosphatidylinositol 3-Kinases; D011991:Receptors, Virus; C491143:HAVCR1 protein, human