Heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates the abundance of the copper-transporter ATP7A in an isoform-dependent manner

• Published in: Frontiers in molecular biosciences 2022-12, Vol.9, p.1067490-1067490
• Main Authors: McCann, Courtney J, Hasan, Nesrin M, Padilla-Benavides, Teresita, Roy, Shubhrajit, Lutsenko, Svetlana
• Format: Article
• Language: English
• Subjects: ATP7A; copper; hnRNPA2/B1; hnRNPA2/B1 regulates ATP7A abundance heterogeneous nuclear ribonucleoprotein (hnRNP); Molecular Biosciences; post-transcriptional regulation; SH-SY5Y cells
• ISSN: 2296-889X; 2296-889X
• DOI: 10.3389/fmolb.2022.1067490

Copper (Cu) is an essential micronutrient with a critical role in mammalian growth and development. Imbalance of Cu causes severe diseases in humans; therefore, cellular Cu levels are tightly regulated. Major Cu-transport proteins and their cellular behavior have been characterized in detail, whereas their regulation at the mRNA level and associated factors are not well-understood. We show that the heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates Cu homeostasis by modulating the abundance of Cu(I)-transporter ATP7A. Downregulation of hnRNPA2/B1 in HeLa cells increases the mRNA and protein levels and significantly decreases cellular Cu; this regulation involves the 3' UTR of ATP7A transcript. Downregulation of B1 and B1b isoforms of hnRNPA2/B1 is sufficient to elevate , whereas overexpression of either hnRNPA2 or hnRNPB1 isoforms decreases the mRNA levels. Concurrent decrease in hnRNPA2/B1, increase in ATP7A, and a decrease in Cu levels was observed in neuroblastoma SH-SY5Y cells during retinoic acid-induced differentiation; this effect was reversed by overexpression of B1/B1b isoforms. We conclude that hnRNPA2/B1 is a new isoform-specific negative regulator of ATP7A abundance.