BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta: Implications for a proteasome-to-autophagy switch

Melania Minoia, Alessandra Boncoraglio, Jonathan Vinet, Federica F. Morelli, Jeanette F. Brunsting, Angelo Poletti, Sabine Krom, Eric Reits, Harm H. Kampinga, Serena Carra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

78 Citations (Scopus)

Abstract

Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome. Therefore, we propose that following proteasome impairment, increasing the BAG3/BAG1 ratio ensures the "BAG-instructed proteasomal to autophagosomal switch and sorting" (BIPASS).

Original languageEnglish
Pages (from-to)1603-1621
Number of pages19
JournalAutophagy
Volume10
Issue number9
DOIs
Publication statusPublished - Sep-2014

Keywords

  • BAG3
  • ubiquitinated proteins
  • proteasome inhibition
  • autophagy linkers
  • PROTEIN-DEGRADATION PATHWAYS
  • NF-KAPPA-B
  • ENDOPLASMIC-RETICULUM STRESS
  • HEAT-SHOCK
  • MOLECULAR CHAPERONES
  • MISFOLDED PROTEINS
  • SELECTIVE AUTOPHAGY
  • QUALITY-CONTROL
  • IN-VIVO
  • PROTEOTOXIC STRESS

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