Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

Supansa Pantoom
,
Adam Pomorski
ORCID logo ,
Katharina Huth
,
Christina Hund
,
Janine Petters
,
Artur Krezel
ORCID logo ,
Andreas Hermann
ORCID logo ,
Jan Lukas
*
Version 1 : Received: 7 October 2021 / Approved: 8 October 2021 / Online: 8 October 2021 (11:06:51 CEST)

A peer-reviewed article of this Preprint also exists.

Pantoom, S.; Pomorski, A.; Huth, K.; Hund, C.; Petters, J.; Krężel, A.; Hermann, A.; Lukas, J. Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy. Cells 2021, 10, 3118. Pantoom, S.; Pomorski, A.; Huth, K.; Hund, C.; Petters, J.; Krężel, A.; Hermann, A.; Lukas, J. Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy. Cells 2021, 10, 3118.

Abstract

Macroautophagy/autophagy plays an important role in cellular copper clearance. The means by which the copper metabolism and autophagy pathways interact mechanistically is vastly unexplored. Dysfunctional ATP7B, a copper-transporting ATPase, is involved in the development of monogenic Wilson disease, a disorder characterized by disturbed copper transport. Using in silico prediction, we found that ATP7B contains a number of potential binding sites for LC3, a central protein in autophagy pathway, so-called LC3 interaction regions (LIRs). The conserved LIR3, located at the C-terminal end of ATP7B, was found to directly interact with LC3B in vitro. Replacing the two conserved hydrophobic residues W1452 and L1455 of LIR3 significantly reduced interaction. Furthermore, autophagy was induced in normal human hepatocellular carcinoma cells (HepG2) leading to enhanced colocalization of ATP7B and LC3B on the autophagosome membranes. By contrast, HepG2 cells deficient of ATP7B (HepG2 ATP7B-/-) showed autophagy deficiency at elevated copper condition. This phenotype was complemented by heterologous ATP7B expression. These findings suggest a cooperative role of ATP7B and LC3B in autophagy-mediated copper clearance.

Keywords

Wilson disease; ATPase copper transporting beta; autophagosome-lysosome fusion; HepG2; LC3 interaction region

Subject

Medicine and Pharmacology, Pathology and Pathobiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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