Journal Article

DZNE-2022-00268

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy.

Pantoom, S. ; Pomorski, A. ; Huth, K. ; Hund, C. ; Petters, J. ; Krężel, A. ; Hermann, A.DZNE* ; Lukas, J.

2021
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/cells10113118

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 the autophagy pathway, the 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.

Keyword(s): Amino Acid Sequence (MeSH) ; Biological Transport: drug effects (MeSH) ; Copper: metabolism (MeSH) ; Copper: pharmacology (MeSH) ; Copper-Transporting ATPases: chemistry (MeSH) ; Copper-Transporting ATPases: metabolism (MeSH) ; Hep G2 Cells (MeSH) ; Humans (MeSH) ; Microtubule-Associated Proteins: metabolism (MeSH) ; Protein Binding: drug effects (MeSH) ; Protein Transport: drug effects (MeSH) ; ATPase copper transporting beta ; HepG2 ; LC3 interaction region ; Wilson disease ; autophagosome-lysosome fusion ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; Copper ; ATP7B protein, human ; Copper-Transporting ATPases

Note: (CC BY)

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Contributing Institute(s):

1. Clinical Dementia Research Rostock /Greifswald (AG Teipel)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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