Author:
Fallatah Arwa,Anastasakis Dimitrios G.,Manzourolajdad Amirhossein,Sharma Pooja,Wang Xiantao,Jacob Alexis,Alsharif Sarah,Elgerbi Ahmed,Coulombe Pierre A.,Hafner Markus,Chung Byung Min
Abstract
Abstract
Background
Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on post-transcriptional gene regulation remain uncharacterized.
Results
Here we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We comprehensively mapped HNRNPK binding sites on mRNAs and showed that, in the cytoplasm, K19-mediated HNRNPK-retention increases the abundance of target mRNAs bound to the 3’ untranslated region (3’UTR) at the expected cytidine-rich (C-rich) sequence elements. Furthermore, these mRNAs protected by HNRNPK in the cytoplasm are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown (HNRNPK KD) or K19 knockout (KRT19 KO).
Conclusions
This study identifies how a cytoskeletal protein can directly regulate gene expression by controlling the subcellular localization of RNA-binding proteins to support pathways involved in cancer progression.
Funder
National Cancer Institute
National Institute for Arthritis and Musculoskeletal and Skin Diseases
National Institute for Arthritis, Musculoskeletal and Skin diseases
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology
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