NFKappaB and Proteostasis

K63-linked ubiquitination and neurodegeneration
Neurobiol. Dis. 2010, view full abstract in PubMed

The proteasome, which identifies and destroys unwanted proteins rapidly, plays a vital role in maintaining cellular protein homeostasis. Proteins that are destined for proteasome-mediated degradation are usually tagged with a chain of ubiquitin linked via lysine (K)48 that targets them to the proteolytic machinery. However, when the proteasome becomes compromised in its function, it is attractive to think that the cell may switch to an alternative, non-proteolytic form of ubiquitination that could help divert cargo proteins away from an otherwise overloaded proteasome. Of the several types of ubiquitin chain topologies, K63-linked ubiquitination is the only one known to fulfil diverse proteasome-independent roles, including DNA repair, endocytosis and NFkappaB signaling. By virtue of its apparent dissociation from the proteasome, we have originally proposed that K63-linked ubiquitination may be involved in cargo diversion during proteasomal stress and accordingly, in the biogenesis of inclusion bodies associated with neurodegenerative diseases. Here, we provide an overview of this non-classic form of ubiquitin modification, and discuss current evidence and controversies surrounding our proposed role for K63 polyubiquitin as a key regulator of inclusion dynamics that is relevant to neurodegeneration.