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Fig. 1 | Cellular & Molecular Biology Letters

Fig. 1

From: p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation

Fig. 1

The interactions of p62 and the UPS, autophagy and ubiquitinated proteins. Upon UPS inhibition, p62 is upregulated and phosphorylated on S405 and S409, which can facilitate the degradation of ubiquitinated cargoes via autophagy. p62 synthesis is induced by an increase in Nrf2 following UPS deficiency. The increased p62 competes with Nrf2 for Keap1, and then a p62–Keap1 complex selectively facilitates the ubiquitinated aggregate formation and creates a positive feedback loop with Nrf2. HDAC6 can be activated by the products in UPS (such as K63), but inhibited directly by p62. HDAC6 plays a critical role in ubiquitinated aggregate formation and autophagosome–lysosome fusion, while a ratio of p62 to HDAC6 maintains the homeostasis of autophagic process. Besides inhibiting the degradation of p62 and ubiquitinated proteins, a deficiency in autophagy also compromises UPS since the increased p62 delays ubiquitinated protein delivery to UPS for degradation. p62 overexpression increases the aggregation of ubiquitinated proteins and has a protective effect on cell survival, while p62 deletion exacerbates cell injury and relates to some diseases by either facilitating or damaging autophagic degradation dependent on the cell type

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