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Loss of ubiquitinated protein autophagy is compensated by persistent cnc/NFE2L2/Nrf2 antioxidant responses

Arindam Bhattacharjee1, Adél Ürmösi1,2, András Jipa1

  • 1Institute of Genetics; Biological Research Centre; Szeged, Hungary.

Autophagy
|February 21, 2022
PubMed

Insights

Selective autophagy receptors link ubiquitinated proteins for degradation. Disrupting this in flies surprisingly activates antioxidant pathways, suggesting aggregation-induced responses compensate for impaired protein clearance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Selective autophagy receptors (SARs) like SQSTM1/p62 are crucial for degrading poly-ubiquitinated protein aggregates by linking them to LC3/Atg8 proteins.
  • The physiological significance of poly-ubiquitinated aggregate accumulation, often observed in human diseases, due to impaired autophagy remains unclear.

Purpose of the Study:

  • To investigate the physiological relevance of ubiquitinated protein autophagy and the consequences of its disruption in a genetically defined model system.
  • To elucidate the mechanisms underlying the accumulation of poly-ubiquitinated aggregates and their impact on cellular pathways.

Main Methods:

  • Utilized a genetically non-redundant *Drosophila* model to specifically disrupt ubiquitinated protein autophagy.
  • Analyzed the effects on bulk autophagy, proteasome activity, healthspan, and the activation of the cap-n-collar/NFE2L2/Nrf2 (cnc/NFE2L2/Nrf2) antioxidant pathway.

Main Results:

  • Specific disruption of ubiquitinated protein autophagy and aggregate formation had minimal impact on bulk autophagy, proteasome activity, and fly healthspan.
  • A mutation disrupting the binding of ref(2)P/SQSTM1 to Atg8a led to Keap1 sequestration, activating the cnc/NFE2L2/Nrf2 antioxidant pathway.
  • Mutant flies exhibited increased oxidative stress tolerance and reduced aging-associated mitochondrial superoxide levels.
  • Ubiquitin overexpression in ref(2)P mutants prevented large aggregate formation and restored cargo recognition but did not abolish antioxidant response activation.

Conclusions:

  • Impaired ubiquitinated protein autophagy can be compensated by an aggregation-induced antioxidant response, mitigating potential detrimental effects.
  • The study highlights a novel compensatory mechanism involving the activation of antioxidant pathways in response to disrupted selective autophagy.
Keywords:
Autophagic receptorDrosophilaautophagylongevityoxidative stress

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