Extracellular mRNA transported to the nucleus exerts translation-independent function

• Published in: Nature communications Vol. 12; no. 1; pp. 3655 - 19
• Main Authors: Tomita, Takeshi, Kato, Masayoshi, Mishima, Taishi, Matsunaga, Yuta, Sanjo, Hideki, Ito, Ken-ichi, Minagawa, Kentaro, Matsui, Toshimitsu, Oikawa, Hiroyuki, Takahashi, Satoshi, Takao, Toshifumi, Iwai, Noriki, Mino, Takashi, Takeuchi, Osamu, Maru, Yoshiro, Hiratsuka, Sachie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 14/19; 3' Untranslated regions; 38/61; 38/71; 38/77; 631/67/327; 631/80/86/820; 82/29; Cell membranes; Extracellular vesicles; Gene expression; Humanities and Social Sciences; IL-1β; Interferon; Interleukin 1; multidisciplinary; Natural killer cells; Nuclei (cytology); Protein transport; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Translation; Vesicles; Zinc; Zinc finger proteins; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23969-1

RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether “naked nonvesicular extracellular mRNA” (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex- interleukin-1β ( IL1β )-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3′-untranslated region of nex- IL1β -mRNA and transports it to the nucleus. The nex- IL1β -mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA. Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.