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Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans
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A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ

Dan Zhang1,2, Yutong Liu1, Yezhang Zhu1

  • 1The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Nature Cell Biology
|May 2, 2022
PubMed

Insights

Scientists discovered a new innate immune pathway involving STING and PERK that controls protein translation and is crucial for cellular senescence and organ fibrosis, offering potential therapeutic targets.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is vital for innate immunity, detecting microbial DNA and cellular damage.
  • Its role in rapidly adapting cellular physiology and its precise mechanisms remain incompletely understood.
  • The cGAS-STING pathway is implicated in infectious diseases, autoimmune disorders, and cancer.

Purpose of the Study:

  • To elucidate the mechanisms by which DNA sensing rapidly shapes cellular physiology.
  • To identify novel components and functions of the cGAS-STING innate immune pathway.
  • To investigate the role of this pathway in cellular senescence and organ fibrosis.

Main Methods:

  • Investigated the interaction between STING and PERK (PKR-like endoplasmic reticulum kinase) in response to cGAMP.
  • Analyzed the phosphorylation of eIF2α downstream of PERK activation.
  • Utilized pharmacological and genetic approaches to target the STING-PERK-eIF2α pathway in models of lung and kidney fibrosis.

Main Results:

  • Identified a novel STING-PERK-eIF2α pathway, distinct from the canonical TBK1-IRF3 axis and unfolded protein response.
  • Demonstrated that activated STING directly binds and activates ER-resident PERK.
  • Showed that this pathway promotes an inflammatory and survival-biased mRNA translation program.
  • Confirmed the pathway's evolutionary primitiveness and critical role in cellular senescence and organ fibrosis.
  • Observed that targeting this pathway attenuated lung and kidney fibrosis.

Conclusions:

  • The STING-PERK-eIF2α pathway represents a previously unrecognized mechanism of innate immunity controlling cap-dependent translation.
  • This pathway plays a critical role in the pathogenesis of organ fibrosis.
  • Targeting the STING-PERK pathway offers a potential therapeutic strategy for fibrotic diseases.

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