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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

77 Citaten (Scopus)

Samenvatting

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).

Originele taal-2English
Pagina's (van-tot)1603-1621
Aantal pagina's19
TijdschriftAutophagy
Volume10
Nummer van het tijdschrift9
DOI's
StatusPublished - sep-2014

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