Molecules and Cells

  • 제45권11호
  • /
  • Pages.855-867
  • /
  • 2022
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons

  • Cho, Jae Ho (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Jo, Min Gu (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Kim, Eun Seon (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Lee, Na Yoon (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Kim, Soon Ha (MitoImmune Therapeutics Inc.) ;
  • Chung, Chang Geon (Department of Neurology, Johns Hopkins University School of Medicine) ;
  • Park, Jeong Hyang (MitoImmune Therapeutics Inc.) ;
  • Lee, Sung Bae (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
  • 투고 : 2022.06.03
  • 심사 : 2022.07.28
  • 발행 : 2022.11.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

For proper function of proteins, their subcellular localization needs to be monitored and regulated in response to the changes in cellular demands. In this regard, dysregulation in the nucleocytoplasmic transport (NCT) of proteins is closely associated with the pathogenesis of various neurodegenerative diseases. However, it remains unclear whether there exists an intrinsic regulatory pathway(s) that controls NCT of proteins either in a commonly shared manner or in a target-selectively different manner. To dissect between these possibilities, in the current study, we investigated the molecular mechanism regulating NCT of truncated ataxin-3 (ATXN3) proteins of which genetic mutation leads to a type of polyglutamine (polyQ) diseases, in comparison with that of TDP-43. In Drosophila dendritic arborization (da) neurons, we observed dynamic changes in the subcellular localization of truncated ATXN3 proteins between the nucleus and the cytosol during development. Moreover, ectopic neuronal toxicity was induced by truncated ATXN3 proteins upon their nuclear accumulation. Consistent with a previous study showing intracellular calcium-dependent NCT of TDP-43, NCT of ATXN3 was also regulated by intracellular calcium level and involves Importin α3 (Imp α3). Interestingly, NCT of ATXN3, but not TDP-43, was primarily mediated by CBP. We further showed that acetyltransferase activity of CBP is important for NCT of ATXN3, which may acetylate Imp α3 to regulate NCT of ATXN3. These findings demonstrate that CBP-dependent acetylation of Imp α3 is crucial for intracellular calcium-dependent NCT of ATXN3 proteins, different from that of TDP-43, in Drosophila neurons.

키워드

과제정보

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (2022R1A4A2000703 and 2021R1A2C1003817) and the Korea Brain Research Institute (KBRI) Research Program (22-BR-03-02), funded by the Ministry of Science and ICT, Republic of Korea, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HU21C0027).

참고문헌

  1. Bagur, R. and Hajnoczky, G. (2017). Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol. Cell 66, 780-788. https://doi.org/10.1016/j.molcel.2017.05.028
  2. Bannister, A.J. and Kouzarides, T. (1996). The CBP co-activator is a histone acetyltransferase. Nature 384, 641-643. https://doi.org/10.1038/384641a0
  3. Bannister, A.J., Miska, E.A., Gorlich, D., and Kouzarides, T. (2000). Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr. Biol. 10, 467-470. https://doi.org/10.1016/S0960-9822(00)00445-0
  4. Bauer, N.C., Doetsch, P.W., and Corbett, A.H. (2015). Mechanisms regulating protein localization. Traffic 16, 1039-1061. https://doi.org/10.1111/tra.12310
  5. Bichelmeier, U., Schmidt, T., Hubener, J., Boy, J., Ruttiger, L., Habig, K., Poths, S., Bonin, M., Knipper, M., Schmidt, W.J., et al. (2007). Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J. Neurosci. 27, 7418-7428. https://doi.org/10.1523/JNEUROSCI.4540-06.2007
  6. Bootman, M.D. and Bultynck, G. (2020). Fundamentals of cellular calcium signaling: a primer. Cold Spring Harb. Perspect. Biol. 12, a038802. https://doi.org/10.1101/cshperspect.a038802
  7. Breuer, P., Haacke, A., Evert, B.O., and Wullner, U. (2010). Nuclear aggregation of polyglutamine-expanded ataxin-3: fragments escape the cytoplasmic quality control. J. Biol. Chem. 285, 6532-6537. https://doi.org/10.1074/jbc.M109.036335
  8. Chung, C.G., Kwon, M.J., Jeon, K.H., Hyeon, D.Y., Han, M.H., Park, J.H., Cha, I.J., Cho, J.H., Kim, K., Rho, S., et al. (2017). Golgi outpost synthesis impaired by toxic polyglutamine proteins contributes to dendritic pathology in neurons. Cell Rep. 20, 356-369. https://doi.org/10.1016/j.celrep.2017.06.059
  9. Chung, C.G., Lee, H., and Lee, S.B. (2018). Mechanisms of protein toxicity in neurodegenerative diseases. Cell. Mol. Life Sci. 75, 3159-3180. https://doi.org/10.1007/s00018-018-2854-4
  10. Evert, B.O., Wullner, U., Schulz, J.B., Weller, M., Groscurth, P., Trottier, Y., Brice, A., and Klockgether, T. (1999). High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Hum. Mol. Genet. 8, 1169-1176. https://doi.org/10.1093/hmg/8.7.1169
  11. Fujigasaki, H., Uchihara, T., Koyano, S., Iwabuchi, K., Yagishita, S., Makifuchi, T., Nakamura, A., Ishida, K., Toru, S., Hirai, S., et al. (2000). Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains. Exp. Neurol. 165, 248-256. https://doi.org/10.1006/exnr.2000.7479
  12. Gaub, P., Tedeschi, A., Puttagunta, R., Nguyen, T., Schmandke, A., and Di Giovanni, S. (2010). HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAFdependent p53 acetylation. Cell Death Differ. 17, 1392-1408. https://doi.org/10.1038/cdd.2009.216
  13. Haacke, A., Broadley, S.A., Boteva, R., Tzvetkov, N., Hartl, F.U., and Breuer, P. (2006). Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum. Mol. Genet. 15, 555-568. https://doi.org/10.1093/hmg/ddi472
  14. Han, M.H., Kwon, M.J., Ko, B.S., Hyeon, D.Y., Lee, D., Kim, H.J., Hwang, D., and Lee, S.B. (2020). NF-kappa B disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases. J. Cell Biol. 219, e202004107. https://doi.org/10.1083/jcb.202004107
  15. Hwang, I.C., Kim, J.Y., Kim, J.H., Lee, J.E., Seo, J.Y., Lee, J.W., Park, J., Yang, H.M., Kim, S.H., Cho, H.J., et al. (2018). Therapeutic potential of a novel necrosis inhibitor, 7-amino-indole, in myocardial ischemia-reperfusion injury. Hypertension 71, 1143-1155. https://doi.org/10.1161/HYPERTENSIONAHA.117.09405
  16. Kim, E.S., Chung, C.G., Park, J.H., Ko, B.S., Park, S.S., Kim, Y.H., Cha, I.J., Kim, J., Ha, C.M., Kim, H.J., et al. (2021). C9orf72-associated argininerich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons. Hum. Mol. Genet. 30, 1084-1100. https://doi.org/10.1093/hmg/ddab089
  17. Kwon, M.J., Han, M.H., Bagley, J.A., Hyeon, D.Y., Ko, B.S., Lee, Y.M., Cha, I.J., Kim, S.Y., Kim, D.Y., Kim, H.M., et al. (2018). Coiled-coil structuredependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects (vol 115, pg E10748, 2018). Proc. Natl. Acad. Sci. U. S. A. 115, E11563.
  18. Lee, D., Lee, Y.I., Lee, Y.S., and Lee, S.B. (2020). The mechanisms of nuclear proteotoxicity in polyglutamine spinocerebellar ataxias. Front. Neurosci. 14, 489. https://doi.org/10.3389/fnins.2020.00489
  19. Lee, S.B., Bagley, J.A., Lee, H.Y., Jan, L.Y., and Jan, Y.N. (2011). Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 108, 16795-16800. https://doi.org/10.1073/pnas.1113573108
  20. Nijman, S.M., Luna-Vargas, M.P., Velds, A., Brummelkamp, T.R., Dirac, A.M., Sixma, T.K., and Bernards, R. (2005). A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773-786. https://doi.org/10.1016/j.cell.2005.11.007
  21. Park, J.H., Chung, C.G., Park, S.S., Lee, D., Kim, K.M., Jeong, Y., Kim, E.S., Cho, J.H., Jeon, Y.M., Shen, C.J., et al. (2020a). Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin alpha3. Elife 9, e60132. https://doi.org/10.7554/eLife.60132
  22. Park, J.H., Chung, C.G., Seo, J., Lee, B.H., Lee, Y.S., Kweon, J.H., and Lee, S.B. (2020b). C9orf72-associated arginine-rich dipeptide repeat proteins reduce the number of Golgi outposts and dendritic branches in Drosophila neurons. Mol. Cells 43, 821-830.
  23. Park, J.H., Kim, H.K., Jung, H., Kim, K.H., Kang, M.S., Hong, J.H., Yu, B.C., Parks, S., Seo, S.K., Choi, I.W., et al. (2017). NecroX-5 prevents breast cancer metastasis by AKT inhibition via reducing intracellular calcium levels. Int. J. Oncol. 50, 185-192. https://doi.org/10.3892/ijo.2016.3789
  24. Peng, L., Peng, Y., Chen, Z., Wang, C., Long, Z., Peng, H., Shi, Y., Shen, L., Xia, K., Leotti, V.B., et al. (2022). The progression rate of spinocerebellar ataxia type 3 varies with disease stage. J. Transl. Med. 20, 226. https://doi.org/10.1186/s12967-022-03428-1
  25. Perez, M.K., Paulson, H.L., and Pittman, R.N. (1999). Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix. Hum. Mol. Genet. 8, 2377-2385. https://doi.org/10.1093/hmg/8.13.2377
  26. Reina, C.P., Zhong, X.Y., and Pittman, R.N. (2010). Proteotoxic stress increases nuclear localization of ataxin-3. Hum. Mol. Genet. 19, 235-249. https://doi.org/10.1093/hmg/ddp482
  27. Saha, R.N. and Pahan, K. (2006). HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ. 13, 539-550. https://doi.org/10.1038/sj.cdd.4401769
  28. Saitoh, Y., Fujikake, N., Okamoto, Y., Popiel, H.A., Hatanaka, Y., Ueyama, M., Suzuki, M., Gaumer, S., Murata, M., Wada, K., et al. (2015). p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies. J. Biol. Chem. 290, 1442-1453. https://doi.org/10.1074/jbc.M114.590281
  29. Simoes, A.T., Carmona, V., Duarte-Neves, J., Cunha-Santos, J., and de Almeida, L.P. (2022). Identification of the calpain-generated toxic fragment of ataxin-3 protein provides new avenues for therapy of Machado-Joseph diseasel Spinocerebellar ataxia type 3. Neuropathol. Appl. Neurobiol. 48, e12748. https://doi.org/10.1111/nan.12748
  30. Soutoglou, E., Katrakili, N., and Talianidis, I. (2000). Acetylation regulates transcription factor activity at multiple levels. Mol. Cell 5, 745-751. https://doi.org/10.1016/S1097-2765(00)80253-1
  31. Sowa, A.S., Haas, E., Hubener-Schmid, J., and Lorentz, A. (2022). Ataxin-3, the spinocerebellar ataxia type 3 neurodegenerative disorder protein, affects mast cell functions. Front. Immunol. 13, 870966. https://doi.org/10.3389/fimmu.2022.870966
  32. Tait, D., Riccio, M., Sittler, A., Scherzinger, E., Santi, S., Ognibene, A., Maraldi, N.M., Lehrach, H., and Wanker, E.E. (1998). Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum. Mol. Genet. 7, 991-997. https://doi.org/10.1093/hmg/7.6.991
  33. Thu, V.T., Kim, H.K., Long, L.T., Lee, S.R., Hanh, T.M., Ko, T.H., Heo, H.J., Kim, N., Kim, S.H., Ko, K.S., et al. (2012). NecroX-5 prevents hypoxia/ reoxygenation injury by inhibiting the mitochondrial calcium uniporter (vol 94, pg 342, 2012). Cardiovasc. Res. 95, 134. https://doi.org/10.1093/cvr/cvs179
  34. Warrick, J.M., Morabito, L.M., Bilen, J., Gordesky-Gold, B., Faust, L.Z., Paulson, H.L., and Bonini, N.M. (2005). Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol. Cell 18, 37-48. https://doi.org/10.1016/j.molcel.2005.02.030
  35. Warrick, J.M., Paulson, H.L., Gray-Board, G.L., Bui, Q.T., Fischbeck, K.H., Pittman, R.N., and Bonini, N.M. (1998). Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93, 939-949. https://doi.org/10.1016/S0092-8674(00)81200-3
  36. Wing, C.E., Fung, H.Y.J., and Chook, Y.M. (2022). Karyopherin-mediated nucleocytoplasmic transport. Nat. Rev. Mol. Cell Biol. 23, 307-328. https://doi.org/10.1038/s41580-021-00446-7
  37. Wolterhoff, N., Gigengack, U., and Rumpf, S. (2020). PP2A phosphatase is required for dendrite pruning via actin regulation in Drosophila. EMBO Rep. 21, e48870. https://doi.org/10.15252/embr.201948870