The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis

Nimmanon, Thirayost, Ziliotto, Silvia, Ogle, Olivia, Burt, Anna, Gee, Julia M. W. ORCID: https://orcid.org/0000-0001-6483-2015, Andrews, Glen K., Kille, Pete ORCID: https://orcid.org/0000-0001-6023-5221, Hogstrand, Christer, Maret, Wolfgang and Taylor, Kathryn M. ORCID: https://orcid.org/0000-0002-9576-9490 2020. The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis. Cellular and Molecular Life Sciences 78 , pp. 1781-1798. 10.1007/s00018-020-03616-6

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Abstract

Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of mitosis, confirming the requirement for zinc influx as a trigger of mitosis. The zinc that influxes into cells to trigger mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the mitosis process compared to other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as cancer.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Biosciences
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License.
Publisher:	Springer Verlag
ISSN:	1420-682X
Funders:	Wellcome Trust
Date of First Compliant Deposit:	20 August 2020
Date of Acceptance:	7 August 2020
Last Modified:	25 Oct 2024 15:33
URI:	https://orca.cardiff.ac.uk/id/eprint/134294

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