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

Introduction
bodies, Mallory-Denk bodies, the neurofibrillary tangles of Alzheimer’s disease
and huntingtin aggregates (Zatloukal et al., 2002; Kuusisto et al., 2001; Nagaoka
et al., 2004), although the domain responsible for mediating its localization to ag-
gresomes has yet to be identified. Thus, p62 appears to function as a shuttling
factor which can alternate between the delivery of polyubiquitylated proteins to
either the proteasome or the aggresome or even directly into the autophagosomal
vesicle. Indeed, p62 could be shown to target tau for proteasomal degradation
(Babu et al., 2005), while it was also able to direct mutated huntingtin to the
autophagosome (Bjørkøy et al., 2005).
HDAC6
HDAC6 (histone deacetylase 6) is a cytoplasmatic class II deacetylase (Verdel and
Khochbin, 1999; Yang and Grégoire, 2005) and is responsible for the deactylation
of α-tubulin (Hubbert et al., 2002; Matsuyama et al., 2002; Zhang et al., 2003b),
HSP90 (Bali et al., 2005) and cortactin (Zhang et al., 2007), although it could be
shown to also deacetylate histones in vitro (Haggarty et al., 2003). HDAC6 is
the only member of the histone deacetylase family which encompasses two cat-
alytic domains and presumably does not rely on dimerization to exert its catalytic
function (Zhang et al., 2006b). In addition to its two catalytic domains, HDAC6
possesses a SE14 repeat domain, which acts as a cytoplasmatic retention signal
(Bertos et al., 2004), a dynein binding domain (Kawaguchi et al., 2003) and a C-
terminal BUZ domain, which is able to interact with polyubiquitin chains as well
as monomeric ubiquitin (Seigneurin-Berny et al., 2001; Hook et al., 2002).
Under conditions of misfolded protein stress HDAC6 is able to associate simul-
taneously with the dynein motor complex through its dynein binding domain as
well as with polyubiquitylated proteins through its BUZ domain. Through these
interactions, it is able mediate the relocalization of polyubiquitylated cargo to the
aggresome via retrograde transport along the microtubule network (Kawaguchi
et al., 2003). HDAC6 associates with the chaperone-like AAA ATPase p97/Cdc48
(Seigneurin-Berny et al., 2001), which is also able to associate with the protea-
some and assists in the degradation of misfolded proteins (Römisch, 2006; Rumpf
and Jentsch, 2006). p97/Cdc48 is able to control the fate of misfolded polyubiqui-
tylated proteins by dissociating them from HDAC6 and redirecting them to pro-
teasomal degradation (Boyault et al., 2006). Furthermore, HDAC6 is responsible
for transporting proteins modfied with K63-linked polyubiquitin chains directly to
the aggresome and for subsequent autophagic degradation even under conditions
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