Biology Reference
In-Depth Information
These initial investigations on aggresomes concentrated on the degradation of
damaged or misfolded proteins, and contributed to a view of centrosomes as
command centers where regulators mingle but do not reside (Doxsey
2001
;
Schatten
2008
). However, with respect to proteasomal degradation the centrosome
is more than simply a gathering point for critical regulators or a point of execution
for degradation. In 1999 the 20S proteasome core, 19S and 11S regulatory sub-
units, ubiquitin, and several molecular chaperones were shown to concentrate at
centrosomes and co-fractionate with c-Tubulin independently of aggresome for-
mation (Wigley et al.
1999
), suggesting that all of the protein unfolding and
proteolysis activities required for proteasome-dependent degradation are normally
localized to centrosomes. Indeed, it was soon shown that the proteasomes present
at centrosomes were fully active in protein degradation (Fabunmi et al.
2000
).
Moreover, during mitosis in embryonic stem cell divisions, proteins destined for
degradation are transported along microtubules to the maternal centrosome, so that
these proteins are asymmetrically inherited to produce one daughter cell that is
relatively cleansed of damaged proteins (Fuentealba et al.
2008
). As discussed
below, the proteasome is the site of regulated destruction of many cell cycle
regulators, as well as a site of accumulation for the major regulators of protein
degradation. Because many aspects of centrosome biology are controlled by reg-
ulated proteolysis, it seems likely that the proteasome and its regulators represent
bona fide resident centrosome proteins. Several components of the UPS were
found in the centrosomal proteome (Andersen et al.
2003
), including the ubiquitin
precursor protein UBCEP80, the ubiquitin-activating enzyme UBE1, one beta
subunit of the 20S particle, and seven subunits of the 19S particle. The centro-
somal proteome study classified candidate proteins using a statistical method based
on how closely their fractionation profile correlated to that of bona fide centrosome
proteins (Andersen et al.
2003
). The extraordinarily high correlation of UBE1 with
the centrosome suggests that the core of the UPS is resident at centrosomes.
Moreover, proteolysis appears to play a role in MTOC assembly and function that
is conserved throughout eukaryotes. The budding yeast 19S proteasome cap
subunit Rpt4p (McDonald and Byers
1997
) and the ubiquitin-like Dsk2p have
been shown to be required for the initiation of SPB duplication (Biggins et al.
1996
), and modulating ER-dependent degradation can suppress the SPB duplica-
tion defects caused by mutations that result in misfolding of two transmembrane
SPB proteins (McBratney and Winey
2002
).
8.5 Proteasomal Degradation Pathways at the Centrosome
Classically, proteins to be degraded by the proteasome are first modified by
ubiquitylation, and there is a huge diversity in the motifs that dictate how a
protein is ubiquitylated [reviewed in (Ravid and Hochstrasser
2008
)]. The E3
ligases responsible for the bulk of cell cycle degradation are the RING-type SCF
and
APC/C
(Skaar
and
Pagano
2009
),
although
both
HECT-type
ligases
