Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

Introduction
strongly induced under conditions which lead to the massive generation of mis-
folded proteins, such as heat-shock or oxidative stress (Hendrick and Hartl, 1995;
Bukau et al., 2006).
Proteins which do not pass quality control mechanisms or fail to successfully
complete chaperone-mediated refolding are eventually targeted for proteasomal
degradation through the attachment of a polyubiquitin-chain. This mechanism
has been well established for proteins degraded via the ER-associated degrada-
tion pathway (ERAD), but is also thought to apply to misfolded proteins originat-
ing from the cytoplasm or nucleus (Meusser et al., 2005). The ubiquitin-ligase
CHIP, for example, represents an interesting connnection between the chaperone
machinery and the ubiquitin-proteasome system. It is able to simultaneously as-
sociate with both the proteasome as well as chaperones of the HSC70 family and is
responsible for the polyubiquitinylation of those chaperone substrates which fail
to aquire proper folding (McDonough and Patterson, 2003). Removal of misfolded
proteins by the proteasome, however, is complicated by the fact that substrate un-
folding is a prerequisite for proteasomal degradation. Thus, for misfolded proteins
to be cleared by the proteasome, they need to be present in soluble, monomeric
form. As soon as they aggregate into insoluble polymers, the proteasome is no
longer able to mediate their destruction, resulting in a vicious circle as insolu-
ble protein aggregates in turn are potent inhibitors of proteasomal degradation
(Bence et al., 2001).
Fortunately, cells have evolved a way out of this predicament through the se-
questration of misfolded proteins in a subcellular structure called the aggresome.
The aggresome is a pericentriolar body which forms mainly under conditions of
misfolded protein stress and is encaged by a tight mesh of vimentin filaments,
presumably to prevent its contents from dissociating. In addition, it contains a
large amount of proteins associated with protein refolding or removal, such as
heat-shock proteins or proteasomes (Kopito, 2000; Garcia-Mata et al., 2002). Pri-
marily in the form of microaggregates, misfolded proteins are actively delivered
to the aggresome via dynein-dependent transport along the microtubule network
(Johnston et al., 2002). Although the majority of misfolded proteins is polyubiq-
uitylated prior to their delivery to the aggresome, a small number of proteins can
apparently be targeted without the involvement of ubiquitin, as overexpression of
inherently unstable proteins such as GFP-250 (Garcia-Mata et al., 1999) as well
as mutant SOD (Johnston et al., 2000) or ATP7B (Johnston et al., 1998) leads to
the formation of aggresomes which do not stain positively for polyubiquitin.
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