Journal
HELIYON
Volume 9, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.heliyon.2023.e18885
Keywords
Hypoxia; NLS; Nuclear import; Carbonic anhydrase; Protein glycosylation; Membrane protein
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The human carbonic anhydrase IX (CA IX) is a hypoxia-induced transmembrane protein involved in pH regulation in hypoxic cells. It is frequently expressed in cancer cells and contributes to tumor progression. This study aimed to understand the mechanisms of CA IX subcellular distribution by targeting the C-terminal domain of CA IX through site-directed mutagenesis in the SH-SY5Y cell line. The results suggest that CA IX nuclear translocation depends on its transit through the secretory and endocytic pathways.
The human carbonic anhydrase IX (CA IX) is a hypoxia-induced transmembrane protein belonging to the a-CA enzyme family. It has a crucial role in pH regulation in hypoxic cells and acts by buffering intracellular acidosis induced by hypoxia. Indeed, it is frequently expressed in cancer cells, where it contributes to tumor progression. CA IX is also able to localize in the nucleus, where it contributes to 47S rRNA precursor genes transcription; however, the mechanisms assisting its nuclear translocation still remain unclear. The aim of our study was to deepen the understanding of the mechanisms involved in CA IX subcellular distribution. To this purpose, we implemented a site-directed mutagenesis approach targeting the C-terminal domain of CA IX and evaluated the subcellular distribution of the wild-type and mutant proteins in the SH-SY5Y cell line. The mutant proteins showed impaired binding ability and altered subcellular distribution in both normoxic and hypoxic conditions. Our data suggest that CA IX nuclear translocation depends on its transit through the secretory and the endocytic pathways.
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