TY - JOUR
T1 - Extracellular mRNA transported to the nucleus exerts translation-independent function
AU - Tomita, Takeshi
AU - Kato, Masayoshi
AU - Mishima, Taishi
AU - Matsunaga, Yuta
AU - Sanjo, Hideki
AU - Ito, Ken ichi
AU - Minagawa, Kentaro
AU - Matsui, Toshimitsu
AU - Oikawa, Hiroyuki
AU - Takahashi, Satoshi
AU - Takao, Toshifumi
AU - Iwai, Noriki
AU - Mino, Takashi
AU - Takeuchi, Osamu
AU - Maru, Yoshiro
AU - Hiratsuka, Sachie
N1 - Funding Information:
We thank Drs Kensuke Miyake (The University of Tokyo) and Yasuhiro Furuichi (Gene-Care Research Institute) for helpful discussions. This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (B) 19H03500 (S. H.) and (C)20K06554 (T. Tomita) as well as The Yasuda Medical Foundation (S. H.). This work was performed in part under the Collaborative Research Program of Institute for Protein Research, Osaka University, CR-18-05 (T. Tomita).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23969-1
DO - 10.1038/s41467-021-23969-1
M3 - Article
C2 - 34135341
AN - SCOPUS:85108164629
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3655
ER -
