期刊
AUTOPHAGY
卷 10, 期 9, 页码 1603-1621出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.29409
关键词
BAG3; ubiquitinated proteins; proteasome inhibition; autophagy linkers
类别
资金
- NWO [175-010-2009-023]
- Marie Curie International Reintegration Grant [PIRG-03-GA-2008-230908]
- Rita Levi Montalcini Prize
- AriSLA grant
- Prinses Beatrix Spierfonds/Dutch Huntington Association grant [WAR09-23]
- Senter Novem [IOP-IGE07004]
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).
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