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Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor

Nature Cell Biology volume 12, pages 655–664 (2010)Cite this article

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Abstract

During apoptosis, dying cells are swiftly removed by phagocytes. It is not fully understood how apoptotic cells are recognized by phagocytes. Here we report the identification and characterization of the Caenorhabditis elegans ttr-52 gene, which encodes a transthyretin-like protein and is required for efficient cell corpse engulfment. The TTR-52 protein is expressed in, and secreted from, C. elegans endoderm and clusters around apoptotic cells. Genetic analysis indicates that TTR-52 acts in the cell corpse engulfment pathway mediated by CED-1, CED-6 and CED-7 and affects clustering of the phagocyte receptor CED-1 around apoptotic cells. TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro. TTR-52 is therefore the first bridging molecule identified in C. elegans that mediates recognition of apoptotic cells by crosslinking the PtdSer 'eat me' signal with the phagocyte receptor CED-1.

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Figure 1: ttr-52 is important for cell corpse engulfment in C. elegans.
Figure 2: ttr-52 encodes a secreted, transthyretin-like protein important for cell corpse engulfment.
Figure 3: TTR-52 is expressed in and secreted from intestine cells and binds to the surface of apoptotic cells.
Figure 4: TTR-52 and CED-1 interact and co-localize to apoptotic cells.
Figure 5: Clustering of TTR-52 and CED-1 around apoptotic cells monitored by time-lapse microscopy.
Figure 6: TTR-52 binds surface-exposed PtdSer.
Figure 7: TTR-52 mediates the random removal of neurons with surface-exposed PtdSer.

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Acknowledgements

We thank J. McGhee for the Pges-1GFP construct and T. Blumenthal for comments and discussion on the manuscript. This work was supported by a Burroughs Wellcome Fund Award (D.X.), NIH R01 grants GM59083 and GM79097 (D.X.), and the National High Technology Project 863 of China (X.C.W).

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  1. Weida Li, Dongfeng Zhao, Bin Liu and Yong Shi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, 80309, Co, USA

    Xiaochen Wang, Yong Shi, Hengwen Yang, Xin Geng, Zhihong Shang, Erin Peden & Ding Xue

  2. National Institute of Biological Sciences, No. 7 Sciences Park Road, Zhongguancun Life Sciences Park, 102206, Beijing, China

    Xiaochen Wang, Weida Li, Dongfeng Zhao, Bin Liu, Baohui Chen & Pengfei Guo

  3. Department of Physiology, Tokyo Women's Medical University, School of Medicine, and CREST, JST, 8-1, Kawada-cho, Shinjuku-ku, 162-8666, Tokyo, Japan

    Eriko Kage-Nakadai & Shohei Mitani

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Contributions

X.C.W. and W.D.L. performed most of the genetic and cell biological experiments. D.F.Z. performed both PtdSer binding experiments and in vitro protein interaction assays. Y.S. performed immunoprecipitation experiments in C. elegans. B.L., B.H.C., P.F.G. and X.G. performed some of the genetic and cell biological experiments. H.W.Y. performed the initial in vitro PtdSer binding experiments and E. P. conducted a bioinformatic analysis of TTR family proteins. Z.H.S., E.K.N. and S.M. contributed to the generation of strains. X.C.W. and D.X. designed the experiments and wrote the paper.

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Correspondence to Xiaochen Wang or Ding Xue.

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Wang, X., Li, W., Zhao, D. et al. Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor. Nat Cell Biol 12, 655–664 (2010). https://doi.org/10.1038/ncb2068

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