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in mucous membranes. Hsp105 appears to have a prominent role in early CFTR
folding events and later at the epithelial membrane, employing its holdase activity
(Saxena et al.
2012
). Ineffective folding results in proteasomal degradation of most
CFTR molecules before reaching the plasma membrane. CFTR is targeted for degra-
dation by the dimeric E3-ubiquitin (Ub) ligase CHIP (Meacham et al.
2001
), which
attaches to the C-termini of Hsp70 and Hsp90 and ubiquitylates client proteins (and
Hsp70). In cells, most of the CHIP protein appears to be associated with Bag2 and
Hsp70, which form a large complex that is Ub-ligase-inactive (Dai et al.
2005
).
Binding of Bag2 prevents association of CHIP with the E2 enzyme (Ub donor) Ub-
cH5b (Arndt et al.
2010
; Dai et al.
2005
). In a ternary complex with Hsc70, HspBP1
also inhibits CHIP Ub-ligase activity, however by a different mechanism (Alberti
et al.
2004
), whereas Bag1 collaborates with CHIP in targeting substrate proteins for
proteasomal degradation (Demand et al.
2001
). Therefore Bag2 and HspBP1 might
help to keep CHIP in check while productive protein folding is ongoing.
Because of its considerable holdase capability, Hsp110 appears to play a special
role among the NEFs. All Hsp110 isoforms were found attached to large aggregates
of mutant superoxide dismutase (SOD1) that are a hallmark of Lou Gehrig's Disease
(also named Amyotrophic lateral sclerosis (ALS)), a protein deposition disease in
which the motor neurons degenerate (Wang et al.
2009
).
In vitro
, Hsp105 can sup-
press mutant SOD aggregation to some degree (Yamashita et al.
2007
). A transgenic
mouse lacking Hsp110/Hsp105 was shown to accumulate hyper-phosphorylated tau
protein in an age-dependent manner, which in turn forms neurofibrillary tangles and
causes neurodegeneration similar to Alzheimer's disease. This phenotype was com-
parable to mice deficient in Hsp70, confirming the role for Hsp70ﾷHsp110 com-
plexes in maintaining tau in an unphosphorylated form during aging (Eroglu et al.
2010
). Hsp110 was also enriched in aggregates of an artificial model protein for
protein deposition diseases, ʲ23 (Olzscha et al.
2011
). In a similar functional role
but with a distinct interaction partner, Hsp110 was required to suppress polygluta-
mine-induced cell death in a
Drosophila
model of polyglutamine (polyQ) diseases.
This class of neurodegenerative diseases, which includes Huntington's disease, is
characterized by cellular deposition of aggregated mutant proteins containing ex-
panded polyQ regions. Together with the Hsp40 family member DNAJ-1, Hsp110
protected cells from neural degeneration while either protein expressed alone had
little effect, suggesting an Hsp110ﾷHsp40 complex is required to maintain protein
homeostasis (Kuo et al.
2013
). Hsp105α was also found associated with deposits
of polyQ-androgen receptor in spinal and bulbar muscular atrophy (Kennedy's dis-
ease) (Ishihara et al.
2003
). Interestingly, Hsp110 along with Hsp70 and Hsp40 was
found to form a disaggregase system capable of dissolving amorphous aggregates in
mammalian cells that are resistant to Hsp70 and Hsp40 alone (Rampelt et al.
2012
;
Shorter
2011
). This system seems to partially replace the function of ClpB/Hsp104
proteins found in bacteria, plants and fungi, which together with the Hsp70 sys-
tem remodel large aggregates and amyloids in an ATP-dependent process. Animals
lack cytosolic ClpB/Hsp104 homologs. The most effective system for solubiliza-
tion of aggregates of FLuc and GFP consisted of the isoforms Apg-2, Hsc70 and
Hdj1/DNAJB1. Since the functional interfaces between Hsp110, Hsp70 and Hsp40
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