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

Introduction
A distinct subgroup consists of ubiquitin domain proteins which are character-
ized by the possession of one or more ubiquitin-associated (UBA) domains and
are thought to function as soluble ubiquitin receptors and facilitators of protea-
somal degradation. Members of this family of UBL-UBA domain proteins in-
clude hHR23/Rad23 (Chen and Madura, 2002), hPLIC/ubiquilin/Dsk2 (Funakoshi
et al., 2002), NUB1 (Kito et al., 2001), and Ddi1/Vsm1 (Bertolaet et al., 2001),
which is the only member of this family containing a putative aspartyl protease
domain (Sirkis et al., 2006). Although there are conflicting data, a growing
body of evidence now supports a model in which UBL-UBA proteins function as
proteasome-substrate carriers by binding to the proteasome through their UBL
domain and to polyubiquitylated cargo through their UBA domain(s).
Most of the evidence comes from the study of Rad23, which was originally dis-
covered as a component of nuclear excision repair, and Dsk2. Both proteins could
be shown to interact via their UBL domain with the S5a (Hiyama et al., 1999;
Walters et al., 2002) and S2 (Elsasser et al., 2002) subunits of the proteasome
and with polyubiquitylated cargo through their UBA domains (Chen et al., 2001;
Zhang et al., 2008a). Through genetic studies, which were mostly performed
in yeast, it could be shown that deletion of either of these proteins resulted in
the accumulation of high molecular weight ubiquitin conjugates and impaired
degradation of a limited number of proteasomal substrates (Chen and Madura,
2002; Funakoshi et al., 2002; Rao and Sastry, 2002). It would be expected that
the overexpression of UBL-UBA proteins, in turn, stimulates the degradation of
these substrates, which could indeed be observed in some cases (Funakoshi et al.,
2002; Verma et al., 2004b). However, it appears that the system is highly sen-
sitive to pertubations in the level of UBL-UBA proteins, as their overexpression
often leads to the stabilization, rather than accelerated degradation, of protea-
somal substrates (Kleijnen et al., 2000; Ortolan et al., 2000). This effect can
probably be attributed to the sequestration of polyubiquin chains by an excess
of soluble UBA domain containing proteins, which effectively prevents their as-
sociation with all sorts of ubiquitin-interacting proteins including not only pro-
teasomal subunits (Raasi and Pickart, 2003), but also for example enzymes in-
volved in polyubiquitin-chain assembly (Ortolan et al., 2000), or deubiquitylation
(Hartmann-Petersen et al., 2003). As most manipulations concerning a single
proteasome receptor have only mild effects on the bulk turnover of polyubiquity-
lated proteins, there appears to be a high level of redundancy in the delivery of
polyubiquitylated substrates to the proteasome. Accordingly, only the combined
deletion of the three proteasome receptors Rpn10, Rad23 and Dsk2 results in a
severe (Saeki et al., 2002a) or lethal (Wilkinson et al., 2001) phenotype in yeast.
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