The Role of HSP70 and Its Co-chaperones in Protein Misfolding, Aggregation and Disease - The Networking of Chaperones by Co-chaperones - page 257

and Braakman 2004 ). Mutations in the GRP78/BiP (HSPA5) co-chaperone SIL1
(or BAP, for BiP associated protein) have been identified as causing the multi-
system autosomal recessive disorder Marinesco-Sj￶gren syndrome (MSS; OMIM
248800) (Anttonen et al. 2005 , 2008 ; Senderek et al. 2005 ; Karim et al. 2006 ;
Eriguchi et al. 2008 ; Takahata et al. 2010 ). This disease is a multi-system disor-
der affecting multiple tissues with key features including: cerebellar ataxia, due
to Purkinje and granule cell loss; progressive myopathy and psychomotor delay;
hypotonia; early-onset cataracts; mental retardation and short stature. One report
of a novel SIL1 homozygous premature stop mutation reported the absence cer-
ebellar ataxia in two affected maternal cousins, although cellular atrophy could not
be assessed (Karim et al. 2006 ). Moreover, additional and novel atypical findings
in MSS patients with SIL1 mutations suggest a broader clinical spectrum caused
by SIL1 mutations than previously thought (Ezgu et al. 2014 ). These include fa-
cial dysmorphism and dental abnormalities; coloboma; seizures and diffuse ec-
zemea. The 461 amino acid N-glycosylated SIL1 protein contains an N-terminal
ER targeting sequence and a divergent C-terminal ER retention signal (LLKELR)
(Chung et al. 2002 ). In the ER, SIL1 interacts with the ATPase domain of GRP78/
BiP (HSPA5) and induces ADP release and subsequent exchange for ATP, thus
acting as a nucleotide exchange factor for GRP78/BiP (HSPA5) and regulating the
chaperones substrate binding cycle (Chung et al. 2002 ). SIL1 mutations in MSS
patients include premature stops, frame shifts, splice site mutations and large in-
tragenic deletions (Anttonen et al. 2005 , 2008 ; Senderek et al. 2005 ; Karim et al.
2006 ; Eriguchi et al. 2008 ; Takahata et al. 2010 ).The majority of SIL1 mutations
are truncating mutations that lead to the loss of SIL1 function and the consequent
disruption of ER protein quality control. Using homology mapping and replace-
ment based on the co-crystal structure of the cytosolic BiP/SIL1 homologs HSP70
and HspBP1, SIL1 mutant proteins clustering in the major interaction site (exons
6 and 9) or minor interaction site (exon 10) were predicted to disrupt binding to
GRP78/BiP (HSPA5) and induce protein folding defects in the ER (Anttonen et al.
2005 ; Senderek et al. 2005 ). Mutations affecting the C-terminal ER retention sig-
nal were initially predicted to interfere with the ER localisation through disruption
of the ER retention signal, leading to inappropriate secretion of SIL1 and deple-
tion from the ER. However in contrast, it was recently reported that mutations that
disrupt the ER retention signal result in unstable mutant proteins that either form
large aggregates in the ER or are rapidly degraded by the proteasome, suggesting
that the C-terminal residues of SIL1 are important for its structural integrity and
that the clinical defect is unlikely to arise from depletion of SIL1 from the ER
(Howes et al. 2012 ). Interestingly, prior to the identification of mutations in SIL1
in MSS, a spontaneous recessive mouse mutation, woozy ( wz ), was identified as
being caused by disruption of the mouse SIL1 gene. The wz mouse has an overlap-
ping phenotype with MSS, including adult onset ataxia with loss of cerebellar Pur-
kinje cells (Zhao et al. 2005 ). Affected cells have intracellular protein inclusions in
the ER and nucleus and upregulation of the unfolded protein response (Zhao et al.
2005 ). These data suggest that BiP mediated protein folding is compromised in the
ER of affected cells. SIL1 appears to be ubiquitously expressed, so it is unclear