title: Cross talk between engulfment receptors stabilin-2 and integrin αvβ5 orchestrates engulfment of phosphatidylserine-exposed erythrocytes.
abstract: Efficient cell corpse clearance is critical for health in organisms. Apoptotic cells displaying phosphatidylserine (PS) are recognized by engulfment receptors and ingested through two conserved pathways. In one pathway, engulfment receptor brain-specific angiogenesis inhibitor 1 (BAI-1) or integrin functions upstream of ELMO/DOCK180 and activate the small GTPase Rac1. In the other pathway, engulfment receptor CED-1 or stabilin-2 acts in concert with the adaptor protein GULP to activate Rac1. Stabilin-2, a PS receptor, facilitates phagocytosis of apoptotic cells and mediates the production of anti-inflammatory cytokines. Here, we propose that the stabilin-2 extracellular domain consisting of integrin-binding fasciclin 1 (FAS1) domains coordinates the activities of the two phagocytic pathways via direct interactions with integrin. Interactions between stabilin-2 and integrin were determined using biochemical assays, including coimmunoprecipitation and fluorescence resonance energy transfer (FRET). These interactions appear to have functional relevance, since knockdown of endogenous αvβ5 expression or treatment with a function-blocking αvβ5 antibody significantly decreased stabilin-2-mediated phagocytosis in the absence of soluble factors. Our data collectively suggest that the engulfment receptors of the two phagocytic pathways communicate with each other to orchestrate engulfment of damaged erythrocytes. Coordinated phagocytic signaling would be advantageous for physiological and pathological circumstances that require rapid clearance of abnormal (apoptotic or aged) cells.
authors.affiliation: Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Soyoun
authors.initials: S
authors.lastname: Kim
authors.forename: Seung-Yoon
authors.initials: SY
authors.lastname: Park
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Kim
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Bae
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Pyo
authors.forename: Mina
authors.initials: M
authors.lastname: Hong
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking; D017209:Apoptosis; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004905:Erythrocyte Aging; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D007739:L Cells; D051379:Mice; D008954:Models, Biological; D010587:Phagocytosis / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019138:Antibodies, Blocking; D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; C099818:DOCK1 protein, human; C454119:GULP1 protein, human; D010718:Phosphatidylserines; D034741:RNA, Small Interfering; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C449927:STAB2 protein, human; C064660:integrin alphaVbeta5; D020744:rac GTP-Binding Proteins