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      Mertk Interacts with Tim-4 to Enhance Tim-4-Mediated Efferocytosis

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          Abstract

          Apoptotic cells expressing phosphatidylserine (PS) on their cell surface are directly or indirectly recognized by phagocytes through PS-binding proteins. The PS-binding protein Tim-4 secures apoptotic cells to phagocytes to facilitate the engulfment of apoptotic cells. However, the molecular mechanism by which Tim-4 transduces signals to phagocytes during Tim-4-mediated efferocytosis is incompletely understood. Here, we report that Tim-4 collaborates with Mertk during efferocytosis through a biochemical interaction with Mertk. Proximal localization between the two proteins in phagocytes was observed by immunofluorescence and proximal ligation assays. Physical association between Tim-4 and Mertk, which was mediated by an interaction between the IgV domain of Tim-4 and the fibronectin type-III domain of Mertk, was also detected with immunoprecipitation. Furthermore, the effect of Mertk on Tim-4-mediated efferocytosis was abolished by GST-Mertk FnIII, a soluble form of the fibronectin type-III domain of Mertk that disrupts the interaction between Tim-4 and Mertk. Taken together, the results from our study suggest that a physical interaction between Tim-4 and Mertk is necessary for Mertk to enhance efferocytosis mediated by Tim-4.

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          Most cited references21

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          Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.

          Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.
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            Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells.

            A classic feature of apoptotic cells is the cell-surface exposure of phosphatidylserine (PtdSer) as an "eat me" signal for engulfment. We show that the Xk-family protein Xkr8 mediates PtdSer exposure in response to apoptotic stimuli. Mouse Xkr8(-/-) cells or human cancer cells in which Xkr8 expression was repressed by hypermethylation failed to expose PtdSer during apoptosis and were inefficiently engulfed by phagocytes. Xkr8 was activated directly by caspases and required a caspase-3 cleavage site for its function. CED-8, the only Caenorhabditis elegans Xk-family homolog, also promoted apoptotic PtdSer exposure and cell-corpse engulfment. Thus, Xk-family proteins have evolutionarily conserved roles in promoting the phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane.
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              TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity.

              The TIM (T cell/transmembrane, immunoglobulin, and mucin) gene family plays a critical role in regulating immune responses, including allergy, asthma, transplant tolerance, autoimmunity, and the response to viral infections. The unique structure of TIM immunoglobulin variable region domains allows highly specific recognition of phosphatidylserine (PtdSer), exposed on the surface of apoptotic cells. TIM-1, TIM-3, and TIM-4 all recognize PtdSer but differ in expression, suggesting that they have distinct functions in regulating immune responses. TIM-1, an important susceptibility gene for asthma and allergy, is preferentially expressed on T-helper 2 (Th2) cells and functions as a potent costimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells, and generates an inhibitory signal resulting in apoptosis of Th1 and Tc1 cells. TIM-3 is also expressed on some dendritic cells and can mediate phagocytosis of apoptotic cells and cross-presentation of antigen. In contrast, TIM-4 is exclusively expressed on antigen-presenting cells, where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. TIM molecules thus provide a functional repertoire for recognition of apoptotic cells, which determines whether apoptotic cell recognition leads to immune activation or tolerance, depending on the TIM molecule engaged and the cell type on which it is expressed.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                06 July 2020
                July 2020
                : 9
                : 7
                : 1625
                Affiliations
                [1 ]School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea; byeongjinmoon@ 123456gist.ac.kr (B.M.); iris260@ 123456gist.ac.kr (J.L.); sanga03@ 123456gist.ac.kr (S.-A.L.); alscksgur@ 123456gist.ac.kr (C.M.); hjmoon311@ 123456gist.ac.kr (H.M.); po7322@ 123456gist.ac.kr (D.K.); susuminy@ 123456gist.ac.kr (S.Y.); gmlfk301@ 123456gist.ac.kr (H.M.); jeonjaeseon17@ 123456gist.ac.kr (J.J.)
                [2 ]Center for Cell Mechanobiology, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
                [3 ]Department of Internal Medicine, Chonnam National Univerity, Gwangju 61469, Korea; yejoo@ 123456chonnam.ac.kr
                Author notes
                [* ]Correspondence: daehopark@ 123456gist.ac.kr ; Tel.: +82-62-715-2890
                Author information
                https://orcid.org/0000-0001-8898-7898
                https://orcid.org/0000-0002-2824-490X
                Article
                cells-09-01625
                10.3390/cells9071625
                7408610
                32640697
                96fcbc66-c360-4d55-8ee9-5f6bbe416dfd
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 May 2020
                : 02 July 2020
                Categories
                Article

                efferocytosis,tim-4,mertk,engulfment,apoptosis,phosphatidylserine,receptor

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