Extracellular mRNA transported to the nucleus exerts translation-independent function

Takeshi Tomita, Masayoshi Kato, Taishi Mishima, Yuta Matsunaga, Hideki Sanjo, Ken-ichi Ito, Kentaro Minagawa, Toshimitsu Matsui, Hiroyuki Oikawa, Satoshi Takahashi, Toshifumi Takao, Noriki Iwai, Takashi Mino, Osamu Takeuchi, Yoshiro Maru () and Sachie Hiratsuka ()
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Takeshi Tomita: Shinshu University, School of Medicine
Masayoshi Kato: Shinshu University, School of Medicine
Taishi Mishima: Tokyo Women’s Medical University
Yuta Matsunaga: Tokyo Women’s Medical University
Hideki Sanjo: Shinshu University, School of Medicine
Ken-ichi Ito: Shinshu University, School of Medicine
Kentaro Minagawa: Penn State College of Medicine
Toshimitsu Matsui: Nishiwaki Municipal Hospital
Hiroyuki Oikawa: Tohoku University
Satoshi Takahashi: Tohoku University
Toshifumi Takao: Osaka University
Noriki Iwai: Kyoto University
Takashi Mino: Kyoto University
Osamu Takeuchi: Kyoto University
Yoshiro Maru: Tokyo Women’s Medical University
Sachie Hiratsuka: Shinshu University, School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23969-1

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