- Open Access
p97 complexes as signal integration hubs
© Meyer; licensee BioMed Central Ltd. 2012
- Received: 8 May 2012
- Accepted: 12 June 2012
- Published: 13 June 2012
In the ubiquitin-proteasome system, a subset of ubiquitylated proteins requires the AAA+ ATPase p97 (also known as VCP or Cdc48) for extraction from membranes or protein complexes before delivery to the proteasome for degradation. Diverse ubiquitin adapters are known to link p97 to its client proteins, but two recent papers on the adapter protein UBXD7, including one by Bandau et al. in BMC Biology, suggest that rather than simply linking p97 to ubiquitylated proteins, this adapter may be essential to coordinate ubiquitylation and p97-mediated extraction of the proteasome substrate. These findings add to growing indications of richly diverse roles of adapters in p97-mediated signaling functions.
See research article: http://0-www.biomedcentral.com.brum.beds.ac.uk/1741-7007/10/36
- Core Complex
- Client Protein
- Ubiquitin Chain
- Ubiquitin Binding
- Ubiquitylated Protein
This simple view has been complicated, however, by a number of recent studies, including evidence from the Deshaies group  that p97 adapters can also link p97 to the E3 ligases that ubiquitylate the client proteins; and in two papers following up these studies, Alexandru and colleagues  and Deshaies and colleagues  report findings that add to increasing evidence for a central and far from simple role for p97 complexes in orchestrating the regulation of many cellular processes.
This cofactor diversity also entails complexity in ubiquitin binding. Cofactors including UBXD8, like UBXD7, themselves contain ubiquitin-binding UBA domains that work in addition to the UBDs in the p97-Ufd1-Npl4 core complex that they associate with. Conversely, there are core complexes with adapters that do not contain apparent UBDs: p97-p37 and p97-UBXD1 are such complexes . It is unclear yet if these core complexes contain additional ubiquitin adapters or whether in these cases ubiquitin binding is mediated directly by p97, which can bind ubiquitin itself, albeit weakly.
An important class of cofactors with clear functional implications are the downstream processing factors that include a growing number of deubiquitylating enzymes . They can either remove ubiquitin chains altogether to recycle the client protein by preventing its degradation, or conversely, they can facilitate substrate degradation by editing the ubiquitin chains to make them appropriate for proteasomal targeting. This suggests that p97 also acts as a relay point in ubiquitin-dependent processes that determines the fate of extracted substrates .
Further important implications for functional versatility can be drawn from the recognition that UBXD7 binds not only ubiquitin but also the ubiquitin-like modifier NEDD8. This raises the possibility that adapters may interact also with other ubiquitin-like modifiers, thus increasing the substrate spectrum of p97 and even further establishing it as a decoding and integration hub in far reaching signaling networks. Examples are the binding of the p47 adapter orthologue Shp1 to the ubiquitin-like modifier Atg8 during autophagy, or the association of p97 and Ufd1 with the SUMO system in yeast [9, 10]. Lastly, several cofactors contain discrete but functionally poorly defined domains, including the UAS domain, which are likely to harbor additional functions that will add to the complexity of the system.
p97 is now established as a key element of ubiquitin-regulated processes. Clearly, ubiquitin adapters link p97 to ubiquitylated clients and thus position its function downstream of ubiquitination. However, it is becoming obvious that there is more to p97 complexes than mere substrate binding and extraction and that they constitute signal integration hubs. Much work lies ahead to understand the individual functions of the adapters, how p97 complexes modulate and coordinate events upstream and downstream of p97-mediated extraction and how this is embedded in complex signaling networks.
HM is funded by DFG grants SPP1365/2 and ME1626/3
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