Extracellular mRNA transported to the nucleus exerts translation-independent function

Nat Commun. 2021 Jun 16;12(1):3655. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism*
  • Culture Media, Conditioned / metabolism
  • Endoribonucleases / metabolism
  • Extracellular Space / metabolism*
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Killer Cells, Natural / metabolism
  • Mice
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Messenger / pharmacology
  • RNA-Binding Proteins / metabolism


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Culture Media, Conditioned
  • IL1B protein, human
  • Interleukin-1beta
  • RNA, Messenger
  • RNA-Binding Proteins
  • Endoribonucleases
  • ZC3H12D protein, human