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ZZ-dependent regulation of p62/SQSTM1 in autophagy

Yi Zhang1, Su Ran Mun2, Juan F Linares3

  • 1Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Nature Communications
|October 24, 2018
PubMed

Insights

The ZZ domain of autophagic receptor p62 recognizes arginylated substrates, activating cellular detoxification and stress responses. This interaction is crucial for p62

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Autophagic receptor p62 is vital for cellular detoxification, stress response, and metabolism.
  • p62 dysfunction is implicated in various human diseases.
  • p62 interacts with numerous ligands, including arginylated (Nt-R) substrates.

Purpose of the Study:

  • To elucidate the structural mechanism of Nt-R recognition by the p62 ZZ domain (p62ZZ).
  • To investigate the functional consequences of p62ZZ-Nt-R substrate binding.
  • To understand p62's role in mTORC1 activation and arginine sensing.

Main Methods:

  • Structural analysis of p62ZZ domain interactions.
  • Biochemical assays to study p62 aggregation and macroautophagy.
  • In vitro binding studies to identify regulatory regions within p62.

Main Results:

  • The p62ZZ domain selectively recognizes Nt-R substrates.
  • p62ZZ-Nt-R binding promotes p62 aggregation and macroautophagy.
  • p62 is essential for arginine-induced mTORC1 activation but not a direct arginine sensor.

Conclusions:

  • Structural insights into p62's recognition of arginylated substrates.
  • p62's role in regulating autophagy and cellular stress responses is mediated by its ZZ domain.
  • Identification of a regulatory linker region that may modulate p62 function.

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