Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

The Peroxisomal Localization of Hsd17b4 Is Regulated by Its Interaction with Phosphatidylserine

  • Lee, Sang-Ah (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Lee, Juyeon (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Kim, Kwanhyeong (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Moon, Hyunji (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Min, Chanhyuk (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Moon, Byeongjin (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Kim, Deokhwan (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Yang, Susumin (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Park, Hyunjin (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Lee, Gwangrog (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Park, Raekil (Department of Biomedical Science and Engineering, GIST) ;
  • Park, Daeho (School of Life Sciences, Gwangju Institute of Science and Technology (GIST))
  • Received : 2020.12.07
  • Accepted : 2021.04.05
  • Published : 2021.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Phosphatidylserine (PS), a negatively charged phospholipid exclusively located in the inner leaflet of the plasma membrane, is involved in various cellular processes such as blood coagulation, myoblast fusion, mammalian fertilization, and clearance of apoptotic cells. Proteins that specifically interact with PS must be identified to comprehensively understand the cellular processes involving PS. However, only a limited number of proteins are known to associate with PS. To identify PS-associating proteins, we performed a pulldown assay using streptavidin-coated magnetic beads on which biotin-linked PS was immobilized. Using this approach, we identified Hsd17b4, a peroxisomal protein, as a PS-associating protein. Hsd17b4 strongly associated with PS, but not with phosphatidylcholine or sphingomyelin, and the Scp-2-like domain of Hsd17b4 was responsible for this association. The association was disrupted by PS in liposomes, but not by free PS or the components of PS. In addition, translocation of PS to the outer leaflet of the plasma membrane enriched Hsd17b4 in peroxisomes. Collectively, this study suggests an unexpected role of PS as a regulator of the subcellular localization of Hsd17b4.

Keywords

Acknowledgement

This research was funded by the National Research Foundation of Korea funded by the Korea government (MSIP) (2019R1A2C1006480, 2019R1I1A1A01057419, and 2019R1A4A1028802) and by GIST Research Institute (GRI) ARI grant in 2020.

References

  1. Boada-Romero, E., Martinez, J., Heckmann, B.L., and Green, D.R. (2020). The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398-414.
  2. Choi, Y., Shimogawa, H., Murakami, K., Ramdas, L., Zhang, W., Qin, J., and Uesugi, M. (2006). Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2. Chem. Biol. 13, 241-249. https://doi.org/10.1016/j.chembiol.2005.12.011
  3. Clark, M.R. (2011). Flippin' lipids. Nat. Immunol. 12, 373-375. https://doi.org/10.1038/ni.2024
  4. Elliott, J.I., Surprenant, A., Marelli-Berg, F.M., Cooper, J.C., Cassady-Cain, R.L., Wooding, C., Linton, K., Alexander, D.R., and Higgins, C.F. (2005). Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat. Cell Biol. 7, 808-816. https://doi.org/10.1038/ncb1279
  5. Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L., and Henson, P.M. (1992). Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207-2216.
  6. Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., and Nagata, S. (2002). Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182-187. https://doi.org/10.1038/417182a
  7. Kay, J.G. and Grinstein, S. (2013). Phosphatidylserine-mediated cellular signaling. Adv. Exp. Med. Biol. 991, 177-193. https://doi.org/10.1007/978-94-007-6331-9_10
  8. Lee, J., Park, B., Moon, B., Park, J., Moon, H., Kim, K., Lee, S.A., Kim, D., Min, C., Lee, D.H., et al. (2019). A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin. Cell Death Differ. 26, 1646-1655. https://doi.org/10.1038/s41418-018-0238-9
  9. Lemke, G. (2013). Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, a009076. https://doi.org/10.1101/cshperspect.a009076
  10. Lentz, B.R. (2003). Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Prog. Lipid Res. 42, 423-438. https://doi.org/10.1016/S0163-7827(03)00025-0
  11. Lomasney, J.W., Cheng, H.F., Roffler, S.R., and King, K. (1999). Activation of phospholipase C delta1 through C2 domain by a Ca(2+)-enzymephosphatidylserine ternary complex. J. Biol. Chem. 274, 21995-22001. https://doi.org/10.1074/jbc.274.31.21995
  12. Min, C., Park, J., Kim, G., Moon, H., Lee, S.A., Kim, D., Moon, B., Yang, S., Lee, J., Kim, K., et al. (2020). Tim-4 functions as a scavenger receptor for phagocytosis of exogenous particles. Cell Death Dis. 11, 561. https://doi.org/10.1038/s41419-020-02773-7
  13. Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T., and Nagata, S. (2007). Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435-439. https://doi.org/10.1038/nature06307
  14. Moon, B., Lee, J., Lee, S.A., Min, C., Moon, H., Kim, D., Yang, S., Moon, H., Jeon, J., Joo, Y.E., et al. (2020a). Mertk interacts with Tim-4 to enhance Tim4-mediated efferocytosis. Cells 9, 1625. https://doi.org/10.3390/cells9071625
  15. Moon, H., Min, C., Kim, G., Kim, D., Kim, K., Lee, S.A., Moon, B., Yang, S., Lee, J., Yang, S.J., et al. (2020b). Crbn modulates calcium influx by regulating Orai1 during efferocytosis. Nat. Commun. 11, 5489. https://doi.org/10.1038/s41467-020-19272-0
  16. Nagata, S., Suzuki, J., Segawa, K., and Fujii, T. (2016). Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 23, 952-961. https://doi.org/10.1038/cdd.2016.7
  17. Orr, J.W. and Newton, A.C. (1992). Interaction of protein kinase C with phosphatidylserine. 2. Specificity and regulation. Biochemistry 31, 4667-4673. https://doi.org/10.1021/bi00134a019
  18. Otera, H., Setoguchi, K., Hamasaki, M., Kumashiro, T., Shimizu, N., and Fujiki, Y. (2002). Peroxisomal targeting signal receptor Pex5p interacts with cargoes and import machinery components in a spatiotemporally differentiated manner: conserved Pex5p WXXXF/Y motifs are critical for matrix protein import. Mol. Cell. Biol. 22, 1639-1655. https://doi.org/10.1128/MCB.22.6.1639-1655.2002
  19. Otsuka, M., Kato, N., Ichimura, T., Abe, S., Tanaka, Y., Taniguchi, H., Hoshida, Y., Moriyama, M., Wang, Y., Shao, R.X., et al. (2005). Vitamin K2 binds 17beta-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism. Life Sci. 76, 2473-2482. https://doi.org/10.1016/j.lfs.2004.12.020
  20. Park, D., Han, C.Z., Elliott, M.R., Kinchen, J.M., Trampont, P.C., Das, S., Collins, S., Lysiak, J.J., Hoehn, K.L., and Ravichandran, K.S. (2011). Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477, 220-224. https://doi.org/10.1038/nature10340
  21. Park, D., Tosello-Trampont, A.C., Elliott, M.R., Lu, M., Haney, L.B., Ma, Z., Klibanov, A.L., Mandell, J.W., and Ravichandran, K.S. (2007). BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430-434. https://doi.org/10.1038/nature06329
  22. Pierce, S.B., Walsh, T., Chisholm, K.M., Lee, M.K., Thornton, A.M., Fiumara, A., Opitz, J.M., Levy-Lahad, E., Klevit, R.E., and King, M.C. (2010). Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am. J. Hum. Genet. 87, 282-288. https://doi.org/10.1016/j.ajhg.2010.07.007
  23. Qadri, S.M., Bissinger, R., Solh, Z., and Oldenborg, P.A. (2017). Eryptosis in health and disease: a paradigm shift towards understanding the (patho) physiological implications of programmed cell death of erythrocytes. Blood Rev. 31, 349-361. https://doi.org/10.1016/j.blre.2017.06.001
  24. Ravichandran, K.S. and Lorenz, U. (2007). Engulfment of apoptotic cells: signals for a good meal. Nat. Rev. Immunol. 7, 964-974. https://doi.org/10.1038/nri2214
  25. Riedl, S., Rinner, B., Asslaber, M., Schaider, H., Walzer, S., Novak, A., Lohner, K., and Zweytick, D. (2011). In search of a novel target - phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim. Biophys. Acta 1808, 2638-2645. https://doi.org/10.1016/j.bbamem.2011.07.026
  26. Rival, C.M., Xu, W., Shankman, L.S., Morioka, S., Arandjelovic, S., Lee, C.S., Wheeler, K.M., Smith, R.P., Haney, L.B., Isakson, B.E., et al. (2019). Phosphatidylserine on viable sperm and phagocytic machinery in oocytes regulate mammalian fertilization. Nat. Commun. 10, 4456. https://doi.org/10.1038/s41467-019-12406-z
  27. Sakuragi, T., Kosako, H., and Nagata, S. (2019). Phosphorylation-mediated activation of mouse Xkr8 scramblase for phosphatidylserine exposure. Proc. Natl. Acad. Sci. U. S. A. 116, 2907-2912. https://doi.org/10.1073/pnas.1820499116
  28. Santiago, C., Ballesteros, A., Martinez-Munoz, L., Mellado, M., Kaplan, G.G., Freeman, G.J., and Casasnovas, J.M. (2007). Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27, 941-951. https://doi.org/10.1016/j.immuni.2007.11.008
  29. Segawa, K., Kurata, S., Yanagihashi, Y., Brummelkamp, T.R., Matsuda, F., and Nagata, S. (2014). Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164-1168. https://doi.org/10.1126/science.1252809
  30. Segawa, K. and Nagata, S. (2015). An apoptotic 'eat me' signal: phosphatidylserine exposure. Trends Cell Biol. 25, 639-650. https://doi.org/10.1016/j.tcb.2015.08.003
  31. Stace, C.L. and Ktistakis, N.T. (2006). Phosphatidic acid- and phosphatidylserine-binding proteins. Biochim. Biophys. Acta 1761, 913-926. https://doi.org/10.1016/j.bbalip.2006.03.006
  32. Swairjo, M.A., Concha, N.O., Kaetzel, M.A., Dedman, J.R., and Seaton, B.A. (1995). Ca(2+)-bridging mechanism and phospholipid head group recognition in the membrane-binding protein annexin V. Nat. Struct. Biol. 2, 968-974. https://doi.org/10.1038/nsb1195-968
  33. van Meer, G., Voelker, D.R., and Feigenson, G.W. (2008). Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112-124. https://doi.org/10.1038/nrm2330
  34. Violante, S., Achetib, N., van Roermund, C.W.T., Hagen, J., Dodatko, T., Vaz, F.M., Waterham, H.R., Chen, H., Baes, M., Yu, C., et al. (2019). Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 33, 4355-4364. https://doi.org/10.1096/fj.201801498r
  35. Voges, D., Berendes, R., Burger, A., Demange, P., Baumeister, W., and Huber, R. (1994). Three-dimensional structure of membrane-bound annexin V. A correlative electron microscopy-X-ray crystallography study. J. Mol. Biol. 238, 199-213. https://doi.org/10.1006/jmbi.1994.1281
  36. Wang, Y., Subramanian, M., Yurdagul, A., Jr., Barbosa-Lorenzi, V.C., Cai, B., de Juan-Sanz, J., Ryan, T.A., Nomura, M., Maxfield, F.R., and Tabas, I. (2017). Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171, 331-345.e22. https://doi.org/10.1016/j.cell.2017.08.041
  37. Yurdagul, A., Jr., Subramanian, M., Wang, X., Crown, S.B., Ilkayeva, O.R., Darville, L., Kolluru, G.K., Rymond, C.C., Gerlach, B.D., Zheng, Z., et al. (2020). Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab. 31, 518-533.e10. https://doi.org/10.1016/j.cmet.2020.01.001
  38. Zhu, Z., Chen, J., Wang, G., Elsherbini, A., Zhong, L., Jiang, X., Qin, H., Tripathi, P., Zhi, W., Spassieva, S.D., et al. (2019). Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1864, 1514-1524. https://doi.org/10.1016/j.bbalip.2019.05.017
  39. Zwaal, R.F., Comfurius, P., and Bevers, E.M. (1998). Lipid-protein interactions in blood coagulation. Biochim. Biophys. Acta 1376, 433-453. https://doi.org/10.1016/S0304-4157(98)00018-5