PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs

Mol Cell. 2018 Sep 20;71(6):1051-1063.e6. doi: 10.1016/j.molcel.2018.07.029. Epub 2018 Aug 30.


Protein kinase RNA-activated (PKR) induces immune response by sensing viral double-stranded RNAs (dsRNAs). However, growing evidence suggests that PKR can also be activated by endogenously expressed dsRNAs. Here, we capture these dsRNAs by formaldehyde-mediated crosslinking and immunoprecipitation sequencing and find that various noncoding RNAs interact with PKR. Surprisingly, the majority of the PKR-interacting RNA repertoire is occupied by mitochondrial RNAs (mtRNAs). MtRNAs can form intermolecular dsRNAs owing to bidirectional transcription of the mitochondrial genome and regulate PKR and eIF2α phosphorylation to control cell signaling and translation. Moreover, PKR activation by mtRNAs is counteracted by PKR phosphatases, disruption of which causes apoptosis from PKR overactivation even in uninfected cells. Our work unveils dynamic regulation of PKR even without infection and establishes PKR as a sensor for nuclear and mitochondrial signaling cues in regulating cellular metabolism.

Keywords: Alu; PKR; cell cycle; cellular dsRNAs; fCLIP-seq; high-throughput sequencing; mitochondria; mitochondrial RNAs; retrotransposons; stress response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Nucleus
  • Enzyme Activation
  • Eukaryotic Initiation Factor-2 / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunoprecipitation / methods
  • Mitochondria / genetics
  • Phosphorylation
  • RNA, Double-Stranded / genetics
  • RNA, Mitochondrial / genetics
  • RNA, Mitochondrial / physiology
  • RNA, Untranslated / genetics
  • RNA, Untranslated / physiology
  • Signal Transduction
  • eIF-2 Kinase / immunology
  • eIF-2 Kinase / metabolism*
  • eIF-2 Kinase / physiology*


  • Eukaryotic Initiation Factor-2
  • RNA, Double-Stranded
  • RNA, Mitochondrial
  • RNA, Untranslated
  • EIF2AK2 protein, human
  • eIF-2 Kinase