SQSTM1/p62-mediated autophagy compensates for loss of proteasome polyubiquitin recruiting capacity

Alik Demishtein, Milana Fraiberg, Dikla Berko, Boaz Tirosh, Zvulun Elazar*, Ami Navon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Protein homeostasis in eukaryotic cells is regulated by 2 highly conserved degradative pathways, the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Recent studies revealed a coordinated and complementary crosstalk between these systems that becomes critical under proteostatic stress. Under physiological conditions, however, the molecular crosstalk between these 2 pathways is still far from clear. Here we describe a cellular model of proteasomal substrate accumulation due to the combined knockdown of PSMD4/S5a and ADRM1, the 2 proteasomal ubiquitin receptors. This model reveals a compensatory autophagic pathway, mediated by a SQSTM1/p62-dependent clearance of accumulated polyubiquitinated proteins. In addition to mediating the sequestration of ubiquitinated cargos into phagophores, the precursors to autophagosomes, SQSTM1 is also important for polyubiquitinated aggregate formation upon proteasomal inhibition. Finally, we demonstrate that the concomitant stabilization of steady-state levels of ATF4, a rapidly degraded transcription factor, mediates SQSTM1 upregulation. These findings provide new insight into the molecular mechanisms by which selective autophagy is regulated in response to proteasomal overflow.

Original languageAmerican English
Pages (from-to)1697-1708
Number of pages12
Issue number10
StatePublished - 3 Oct 2017

Bibliographical note

Publisher Copyright:
© 2017 Taylor & Francis.


  • ADRM1/Rpn13
  • SQSTM1/p62
  • autophagy
  • proteasome
  • ubiquitin receptor PSMD4/Rpn10


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