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Research Article
Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner
Santanu Das, Saptarshi Maji, Ruturaj, Indira Bhattacharya, Tanusree Saha, Nabanita Naskar, Arnab Gupta
Journal of Cell Science 2020 133: jcs246819 doi: 10.1242/jcs.246819 Published 24 December 2020
Santanu Das
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Saptarshi Maji
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Ruturaj
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Indira Bhattacharya
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Tanusree Saha
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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Nabanita Naskar
2Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
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Arnab Gupta
1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India
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  • ORCID record for Arnab Gupta
  • For correspondence: arnab.gupta@iiserkol.ac.in

Handling Editor: Mahak Sharma

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ABSTRACT

The Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: A.G., S.D.; Methodology: A.G., S.D., R.R., I.B., T.S., N.N.; Software: S.M.; Validation: A.G., R.R.; Formal analysis: A.G., S.D., S.M.; Investigation: A.G., S.D., T.S.; Resources: A.G., S.D.; Data curation: S.D., R.R., N.N.; Writing - original draft: A.G., S.D.; Writing - review & editing: A.G., S.D.; Visualization: R.R.; Supervision: A.G.; Project administration: A.G.; Funding acquisition: A.G.

  • Funding

    This work was supported by a The Wellcome Trust DBT India Alliance Fellowship (IA/I/16/1/502369) and Early Career Research Award (ECR/2015/000220) from Department of Science and Technology, Ministry of Science and Technology, India (SERB) and IISER K intramural funding to A.G. S.M. and I.B. was supported by Pre-doctoral fellowship from Council of Scientific and Industrial Research, India. T.S. was supported by National Postdoctoral Fellowship, SERB, India. The pre-doctoral fellowship for S.D. is supported by Welcome Trust DBT India Alliance. The predoctoral fellowship for Ruturaj is supported by Intramural Institute funding (IISER-K). The post-doctoral fellowship for N.N. is funded by SINP Intramural funding.

  • Supplementary information

    Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.246819.supplemental

  • Received March 29, 2020.
  • Accepted November 19, 2020.
  • © 2020. Published by The Company of Biologists Ltd
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Keywords

  • ATP7B
  • Retromer
  • VPS35
  • Copper metabolism
  • Endolysosome
  • Wilson disease

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Research Article
Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner
Santanu Das, Saptarshi Maji, Ruturaj, Indira Bhattacharya, Tanusree Saha, Nabanita Naskar, Arnab Gupta
Journal of Cell Science 2020 133: jcs246819 doi: 10.1242/jcs.246819 Published 24 December 2020
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Research Article
Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner
Santanu Das, Saptarshi Maji, Ruturaj, Indira Bhattacharya, Tanusree Saha, Nabanita Naskar, Arnab Gupta
Journal of Cell Science 2020 133: jcs246819 doi: 10.1242/jcs.246819 Published 24 December 2020

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