Figure 11.

Model for long-term UPS inhibition on autophagy in primary astrocytes. Long-term UPS inhibition elicits multiple phenotypes defined by distinct structures and trafficking itineraries for SQSTM1 that may represent different stages in the cellular response. In one population of astrocytes, SQSTM1 is routed to autophagy for proteolytic degradation, resulting in only a modest activation of autophagy. In another population of astrocytes, SQSTM1 is diverted away from degradative compartments to accumulate in aggresomes that are enriched for ubiquitin and cytosolic LC3. Sequestration of cytosolic LC3 may contribute to the reduction in autophagic flux observed in astrocytes with aggresomes.