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). As BAG3, a partner of the heat shock proteins HSPB8 and Hsp70, stimulates autophagy and its levels increase with aging, a condition characterized by decreased proteasome function and autophagy activation, it is tempting to speculate that BAG3 is required to re-route ubiquitinated clients to autophagy. Here, we show that BAG3 interacts via its BAG domain with ubiquitinated proteins and induces their sequestration into cytoplasmic puncta. Similarly, BAG3 drives, in an Hsp70-dependent manner, the recruitment of the proteasome client Ub-R-GFP into similar cytoplasmic puncta. These cytoplasmic puncta are co-labelled with canonical autophagy markers and linkers, suggesting that proteasomal client are re-routed to autophagy by BAG3. Indeed, upon proteasome inhibition ubiquitinated (insoluble) proteins accumulate in control cells, whilst in cells overexpressing BAG3 they are efficiently re-routed to autophagy for clearance. This action might be independent of HSPB8, which we find to dissociate from BAG3 early after proteasomal inhibition. Rather, HSPB8 becomes associated with RNA-containing stress granules, likely participating in translational arrest under proteasomal stress. Upon prolonged proteasomal inhibition, HSPB8 is then also massively recruited to the BAG3-positive puncta, tentatively to contribute to autophagy-mediated protein degradation of (other) accumulating misfolded substrates.
|Data di pubblicazione:||2013|
|Titolo:||BAG3-mediated re-routing of protein degradation towards autophagy upon proteasomal impairment|
|Data del convegno:||18-22 Agosto 2013|
|Nome del convegno:||VI International Congress on Stress Proteins in Biology and Medicine|
|Luogo del convegno:||Sheffield, UK|
|Titolo del libro:||VI International Congress on Stress Proteins in Biology and Medicine|
|Appare nelle tipologie:||Relazione in Atti di Convegno|
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