异质核糖核蛋白 K (HNRNPK) 调控核内的前 mRNA 加工和长非编码 RNA 定位。先前的研究表明，HNRNPK 在穿梭到细胞质时促进了细胞增殖和癌症转移。然而，HNRNPK 细胞质定位的机制、其细胞质 RNA 配体以及对转录后基因调控的影响尚未表征。在这里，我们展示了中间丝蛋白 Keratin 19 (K19) 与 HNRNPK 直接相互作用，并将其困留在细胞质中。相应地，在 K19 基因敲除的乳腺癌细胞中，HNRNPK 不定位于细胞质，导致细胞增殖减少。我们全面地绘制了 HNRNPK 在 mRNA 上的结合位点，并表明，在细胞质中，K19 介导的 HNRNPK 增加了与预期胞嘧啶丰富（C-rich）序列元素结合的靶向 mRNA 在 3' 未翻译区（3'UTR）的丰度。此外，在细胞质中被 HNRNPK 保护的这些 mRNA 通常涉及癌症进展，并包括 p53 信号通路，该通路在 HNRNPK 敲下（HNRNPK KD）或 K19 基因敲除（KRT19 KO）时发生了错调。本研究揭示了细胞骨架蛋白如何通过控制 RNA 结合蛋白的亚细胞定位来直接调节基因表达，支持与癌症进展相关的途径。© 2023 年 BioMed Central Ltd.，Springer Nature 的一部分。

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.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).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.© 2023. BioMed Central Ltd., part of Springer Nature.