Cell signalling is carried out by selec-tive and complex metabolic networks that, when impaired, result in disease. The challenge for the cell is to maintain fidelity during normal processes, while allowing the plasticity that is required to control the complicated machinery of a functional cell. This is achieved through protein hubs that organize the flow of information inside the cell; one such hub is the signalling adapter p62 (Moscat et al, 2006). The identification of p62-interacting proteins, the analysis of knockout (KO) mice, and the fact that p62 mutations are associated with a human disease—Paget bone disease—have confirmed the importance of p62 in homeo static cell function and disease (Moscat et al, 2007). p62 binds to atypical PKCs, the signalling adapter RIP, the E3 ubiquitin ligase TRAF6, the kinase ERK, and caspase 8 through different motifs (Jin et al, 2009; Moscat et al, 2006), thereby eliciting various effects that have been confirmed pheno typically in p62 KO mice. These include alterations in bone physiology, metabolic control and adipogenesis, T lymphocyte function and resistance to cancer (Moscat et al, 2007). p62 is localized in cyto plasmic speckles, where it concentrates and oligo merizes polyubiquitinated signalling proteins to facilitate the efficient activation of prosurvival and pro-apoptotic pathways (Jin et al, 2009; Moscat et al, 2006). This way, p62 emerges as a crucial factor in normal homeostasis and cancer, depending on the specific stimulus and possibly other conditions (Duran et al, 2008). p62 is a target of autophagy (Komatsu et al, 2007), which might modulate the signalling pathways emanating from p62 speckles in metabolically stressed cells. When autophagy is inhibited, p62 speckles become bigger p62-containing aggregates that co-localize with polyubiquitinated, presumably misfolded proteins that are normally degraded by autophagy (Komatsu et al, 2007). A similar pattern is detected in cells in which the proteasome is inhibited, which has led to the hypothesis that the role of p62 under these conditions is to aggregate polyubiquitinated proteins—which can be toxic when soluble—into harmless ‘packages’. When these polyubiquitinated aggregates are formed as a consequence of proteasome inhibition, p62 could deliver them to the autophagosome for degradation. Thus, in addition to its role as a signalling hub, p62 could function in ‘garbage packing’and the eventual disposal of toxic proteins. However, there are several concerns with this proposed role for p62 that need to be addressed. One question is teleological: if the role of p62 is to deliver ‘packaged’toxic proteins for degradation through autophagosomes, why is p62 itself degraded? It does not make ‘economical’sense for the cell to degrade the package and also to kill the delivery guy. Another intriguing question originates from the fact that increased levels of p62 in autophagydeficient cells inhibit the proteasome, leading to the enhanced accumulation of polyubiquitinated proteins as aggregates (Korolchuk et al, 2009). This suggests that, in cells that are deficient in both autophagy and p62, the lack of aggregates is not due to the absence of p62-mediated protein packaging but, rather, because p62 deficiency leads to enhanced proteasome activity, which degrades polyubiquitinated proteins before they can accumulate. A third concern is the toxicity phenotype of the Atg7/p62 double KO mice, as compared with Atg7 KO mice, which is not consistent with the purported role of p62 in alleviating the toxicity of soluble polyubiquitinated proteins. If the role of p62 is to concentrate the toxic proteins into aggregates, the loss of p62 should worsen liver toxicity in the Atg7 KO …