Almost all tissues with defective autophagy are usually displaying an accumulation of polyubiquitinated proteins [149] . Loss of autophagy is considered to lead to a delay in the global turnover of cytoplasmic components [137] and/or to an impaired degradation of substrates destined for the proteasome [167] . Both observations could partially explain the accumulation of misfolded and/or unfolded proteins that is followed by the formation of inclusion bodies. As discussed above, p62 and NBR1 act as autophagy receptors for ubiquitinated cargos such as protein aggregates, mitochondria, midbody rings, bacteria, ribosomal proteins and virus capsids [83, 168] (Figure 3 ). Although these studies suggest the role of p62 as an ubiquitin receptor, it remains to be established whether soluble ubiquitinated proteins are also degraded one-by-one by p62 and possibly NBR1. A mass spectrometric analysis has clearly demonstrated the accumulation of all detectable topologies of ubiquitin chain in Atg deficient livers and brains, indicating that specific polyubiquitin chain linkage is not the decisive signal for autophagic degradation [169] . Because the increase in ubiquitin conjugates in the Atg7 deficient liver and brain is completely suppressed by additional knockout of either p62 or Nrf2 [169] , accumulation of ubiquitinated proteins in tissues defective in autophagy might be attributed to p62mediated activation of Nrf2, resulting in global transcriptional changes to ubiquitin-associated genes. Further studies are needed to precisely elucidate the degradation mechanism of soluble ubiquitinated proteins by autophagy.