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, Sachie Hiratsuka

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3655
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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