A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin
An essential step during clearance of apoptotic cells is the recognition of phosphatidylserine (PS) exposed on apoptotic cells by its receptors on phagocytes. Tim-4 directly binding to PS and functioning as a tethering receptor for phagocytosis of apoptotic cells has been extensively studied over th...
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| Veröffentlicht in: | Cell death and differentiation 2019-09, Vol.26 (9), p.1646-1655 |
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| creator | Lee, Juyeon Park, Boyeon Moon, Byeongjin Park, Jeongjun Moon, Hyunji Kim, Kwanhyeong Lee, Sang-Ah Kim, Deokhwan Min, Chanhyuk Lee, Dae-Hee Lee, Gwangrog Park, Daeho |
| description | An essential step during clearance of apoptotic cells is the recognition of phosphatidylserine (PS) exposed on apoptotic cells by its receptors on phagocytes. Tim-4 directly binding to PS and functioning as a tethering receptor for phagocytosis of apoptotic cells has been extensively studied over the past decade. However, the molecular mechanisms by which Tim-4 collaborates with other engulfment receptors during efferocytosis remain elusive. By comparing efferocytosis induced by Tim-4 with that by Anxa5-GPI, an artificial tethering receptor, we found that Tim-4 possesses auxiliary machinery to induce a higher level of efferocytosis than Anxa5-GPI. To search for that, we performed a yeast two-hybrid screen and identified Fibronectin (Fn1) as a novel Tim-4-associating protein. Tim-4 directly associated with Fn1 and formed a complex with integrins via the association of Fn1. Through Tim-4
−/−
mice and cell-based assays, we found that modulation of the Fn1 level affected efferocytosis induced by Tim-4 and disruption of the interaction between Tim-4 and Fn1 abrogated Tim-4-mediated efferocytosis. In addition, Tim-4 depletion attenuated integrin signaling activation and perturbation of integrin signaling suppressed Tim-4-promoted efferocytosis. Taken together, the data suggest that Fn1 locates Tim-4 and integrins in close proximity by acting as a scaffold, resulting in synergistic cooperation of Tim-4 with integrins for efficient efferocytosis. |
| doi_str_mv | 10.1038/s41418-018-0238-9 |
| format | Article |
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−/−
mice and cell-based assays, we found that modulation of the Fn1 level affected efferocytosis induced by Tim-4 and disruption of the interaction between Tim-4 and Fn1 abrogated Tim-4-mediated efferocytosis. In addition, Tim-4 depletion attenuated integrin signaling activation and perturbation of integrin signaling suppressed Tim-4-promoted efferocytosis. Taken together, the data suggest that Fn1 locates Tim-4 and integrins in close proximity by acting as a scaffold, resulting in synergistic cooperation of Tim-4 with integrins for efficient efferocytosis.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-018-0238-9</identifier><identifier>PMID: 30451988</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/95 ; 14/19 ; 38/1 ; 42/35 ; 42/89 ; 631/337/176 ; 631/45 ; 631/80 ; 82 ; 82/111 ; 96 ; 96/2 ; 96/31 ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Analysis ; Fibronectin ; Integrins ; Life Sciences ; Molecular modelling ; Phagocytes ; Phagocytosis ; Phosphatidylserine ; Stem Cells</subject><ispartof>Cell death and differentiation, 2019-09, Vol.26 (9), p.1646-1655</ispartof><rights>ADMC Associazione Differenziamento e Morte Cellulare 2018</rights><rights>Copyright Nature Publishing Group Sep 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-2432c2bc9273a41b44d98f605f2e68b4829a2c1bd64e1781ee042cafe7fce0b83</citedby><cites>FETCH-LOGICAL-c470t-2432c2bc9273a41b44d98f605f2e68b4829a2c1bd64e1781ee042cafe7fce0b83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748117/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748117/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41488,42557,51319,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30451988$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Juyeon</creatorcontrib><creatorcontrib>Park, Boyeon</creatorcontrib><creatorcontrib>Moon, Byeongjin</creatorcontrib><creatorcontrib>Park, Jeongjun</creatorcontrib><creatorcontrib>Moon, Hyunji</creatorcontrib><creatorcontrib>Kim, Kwanhyeong</creatorcontrib><creatorcontrib>Lee, Sang-Ah</creatorcontrib><creatorcontrib>Kim, Deokhwan</creatorcontrib><creatorcontrib>Min, Chanhyuk</creatorcontrib><creatorcontrib>Lee, Dae-Hee</creatorcontrib><creatorcontrib>Lee, Gwangrog</creatorcontrib><creatorcontrib>Park, Daeho</creatorcontrib><title>A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>An essential step during clearance of apoptotic cells is the recognition of phosphatidylserine (PS) exposed on apoptotic cells by its receptors on phagocytes. Tim-4 directly binding to PS and functioning as a tethering receptor for phagocytosis of apoptotic cells has been extensively studied over the past decade. However, the molecular mechanisms by which Tim-4 collaborates with other engulfment receptors during efferocytosis remain elusive. By comparing efferocytosis induced by Tim-4 with that by Anxa5-GPI, an artificial tethering receptor, we found that Tim-4 possesses auxiliary machinery to induce a higher level of efferocytosis than Anxa5-GPI. To search for that, we performed a yeast two-hybrid screen and identified Fibronectin (Fn1) as a novel Tim-4-associating protein. Tim-4 directly associated with Fn1 and formed a complex with integrins via the association of Fn1. Through Tim-4
−/−
mice and cell-based assays, we found that modulation of the Fn1 level affected efferocytosis induced by Tim-4 and disruption of the interaction between Tim-4 and Fn1 abrogated Tim-4-mediated efferocytosis. In addition, Tim-4 depletion attenuated integrin signaling activation and perturbation of integrin signaling suppressed Tim-4-promoted efferocytosis. Taken together, the data suggest that Fn1 locates Tim-4 and integrins in close proximity by acting as a scaffold, resulting in synergistic cooperation of Tim-4 with integrins for efficient efferocytosis.</description><subject>13/95</subject><subject>14/19</subject><subject>38/1</subject><subject>42/35</subject><subject>42/89</subject><subject>631/337/176</subject><subject>631/45</subject><subject>631/80</subject><subject>82</subject><subject>82/111</subject><subject>96</subject><subject>96/2</subject><subject>96/31</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Fibronectin</subject><subject>Integrins</subject><subject>Life Sciences</subject><subject>Molecular modelling</subject><subject>Phagocytes</subject><subject>Phagocytosis</subject><subject>Phosphatidylserine</subject><subject>Stem 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fibronectin</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>26</volume><issue>9</issue><spage>1646</spage><epage>1655</epage><pages>1646-1655</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>An essential step during clearance of apoptotic cells is the recognition of phosphatidylserine (PS) exposed on apoptotic cells by its receptors on phagocytes. Tim-4 directly binding to PS and functioning as a tethering receptor for phagocytosis of apoptotic cells has been extensively studied over the past decade. However, the molecular mechanisms by which Tim-4 collaborates with other engulfment receptors during efferocytosis remain elusive. By comparing efferocytosis induced by Tim-4 with that by Anxa5-GPI, an artificial tethering receptor, we found that Tim-4 possesses auxiliary machinery to induce a higher level of efferocytosis than Anxa5-GPI. To search for that, we performed a yeast two-hybrid screen and identified Fibronectin (Fn1) as a novel Tim-4-associating protein. Tim-4 directly associated with Fn1 and formed a complex with integrins via the association of Fn1. Through Tim-4
−/−
mice and cell-based assays, we found that modulation of the Fn1 level affected efferocytosis induced by Tim-4 and disruption of the interaction between Tim-4 and Fn1 abrogated Tim-4-mediated efferocytosis. In addition, Tim-4 depletion attenuated integrin signaling activation and perturbation of integrin signaling suppressed Tim-4-promoted efferocytosis. Taken together, the data suggest that Fn1 locates Tim-4 and integrins in close proximity by acting as a scaffold, resulting in synergistic cooperation of Tim-4 with integrins for efficient efferocytosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30451988</pmid><doi>10.1038/s41418-018-0238-9</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell death and differentiation, 2019-09, Vol.26 (9), p.1646-1655 |
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| subjects | 13/95 14/19 38/1 42/35 42/89 631/337/176 631/45 631/80 82 82/111 96 96/2 96/31 Apoptosis Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Fibronectin Integrins Life Sciences Molecular modelling Phagocytes Phagocytosis Phosphatidylserine Stem Cells |
| title | A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin |
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