title: The phosphatidylserine receptor TIM-4 does not mediate direct signaling.
abstract: Engulfment of apoptotic cells is an active process coordinated by receptors on phagocytes and ligands on apoptotic cells [1]. Phosphatidylserine (PtdSer) is a key ligand on apoptotic cells, and recently three PtdSer recognition receptors have been identified, namely, TIM-4, BAI1, and Stabilin-2 [1-6]. Whereas BAI1 is dependent on the ELMO1/Dock180/Rac signaling module, and Stablilin-2 appears to use the intracellular adaptor GULP [2, 3, 7], little is known about how TIM-4 transduces signals downstream of PtdSer recognition [8]. To test the role of known engulfment signaling pathways in TIM-4-mediated engulfment, we used a combination of dominant-negative mutants, knockdown of specific signaling proteins, and knockout cell lines. TIM-4 appears to be largely independent of the two known engulfment signaling pathways [7, 9-17], yet the TIM-4-mediated uptake is inhibited by cytoskeleton disrupting drugs. Remarkably, a version of TIM-4 lacking its cytoplasmic tail promoted corpse uptake via PtdSer recognition. Moreover, replacement of the transmembrane region of TIM-4 with a glycophosphatidylinositol anchor still promoted engulfment comparable to wild-type TIM-4. Thus, the transmembrane region and cytoplasmic tail of TIM-4 are dispensable for apoptotic cell engulfment, and we propose that TIM-4 is a PtdSer tethering receptor without any direct signaling of its own.
authors.affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, 22908, USA.
authors.forename: Daeho
authors.initials: D
authors.lastname: Park
authors.forename: Amelia
authors.initials: A
authors.lastname: Hochreiter-Hufford
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C468226:ADGRB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D042501:Angiogenic Proteins; C465214:ELMO1 protein, human; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C512411:TIMD4 protein, human; C408123:phosphatidylserine receptor; D024462:Myosin Type II