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Extracellular SQSTM1 as an inflammatory mediator

Borong Zou1, Jiao Liu1, Daniel J Klionsky2

  • 1The Third Affiliated Hospital, Guangzhou Medical University , Guangzhou, Guangdong, China.

Autophagy
|October 28, 2020
PubMed

Insights

SQSTM1/p62 (sequestosome 1) acts as a lethal inflammatory mediator in sepsis. Blocking the SQSTM1-INSR pathway reduces sepsis severity and organ damage, offering a potential therapeutic target.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathology

Background:

  • Excessive inflammation is a major cause of sepsis-related mortality.
  • Key mediators and mechanisms driving lethal inflammation in sepsis remain incompletely understood.

Purpose of the Study:

  • To identify novel lethal inflammatory mediators in sepsis.
  • To elucidate the mechanisms of SQSTM1/p62 (sequestosome 1) in sepsis pathogenesis.

Main Methods:

  • Investigated SQSTM1/p62 release mechanisms (passive via pyroptosis, active via STING1/STING/TMEM173 and secretory lysosomes).
  • Examined extracellular SQSTM1-INSR pathway activation, glycolysis, and NF-κB signaling.
  • Utilized genetic deletion and pharmacological inhibition in experimental mouse sepsis models.
  • Correlated pathway activation with sepsis severity in human patients.

Main Results:

  • SQSTM1/p62 is identified as a lethal inflammatory mediator in sepsis and septic shock.
  • Extracellular SQSTM1 binds INSR, activating glycolysis and promoting pro-inflammatory cytokine production via NF-κB.
  • Inhibition of the SQSTM1-INSR pathway ameliorated sepsis-induced tissue damage, inflammation, organ failure, and mortality in mice.
  • SQSTM1-INSR pathway activation correlated with sepsis severity in patients.

Conclusions:

  • Extracellular SQSTM1/p62 plays a critical pathological role in sepsis.
  • The SQSTM1-INSR pathway represents a novel therapeutic target for sepsis and related inflammatory conditions.
Keywords:
AutophagyDAMPINSRSQSTM1STING1TLR4immunometabolisminflammasomesepsis

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