TY - JOUR
T1 - ITCH regulates degradation of mutant glucocerebrosidase
T2 - Implications to gaucher disease
AU - Maor, Gali
AU - Filocamo, Mirella
AU - Horowitz, Mia
N1 - Funding Information:
This work was partially supported by grants from the Israel Ministry of Health and the Israel Science Foundation (to M.H.) and by grants from the Italian Health Department ‘Finanziamento Ricerca Corrente (contributo per la ricerca intramurale)’ (to M.F.).
Funding Information:
We would like to thank Prof. Y. Shaul, Prof. Y. Yarden and Prof. M. Oren (The Weizmann Institute of Science, Rehovot, Israel) for their kind gifts of plasmids and the ‘Cell Line and DNA Biobank from Patients Affected by Genetic Diseases’ (G. Gaslini Institute)—Telethon Genetic Biobank Network (Project No. GTB07001A) for cells.
PY - 2013/4
Y1 - 2013/4
N2 - Inability to properly degrade unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and unfolded protein response. This is particularly important in cases of diseases in which the mutant proteins undergo ER-associated degradation (ERAD), as in Gaucher disease (GD). GD is a genetic, autosomal recessive disease that results from mutations in the GBA1 gene, encoding the lysosomal enzyme acid β-glucocerebrosidase (GCase). We have shown that mutant GCase variants undergo ERAD, the degree of which is a major determinant of disease severity. Most ERAD substrates undergo polyubiquitination and proteasomal degradation. Therefore, one expects that mutant GCase variants are substrates for several E3 ubiquitin ligases in different cells. We tested the possibility that ITCH, a known E3 ubiquitin ligase, with a pivotal role in proliferation and differentiation of the skin, recognizes mutant GCase variants and mediates their polyubiquitination and degradation. Our results strongly suggest that ITCH interacts with mutant GCase variants and mediates their lysine 48 polyubiquitination and degradation.
AB - Inability to properly degrade unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and unfolded protein response. This is particularly important in cases of diseases in which the mutant proteins undergo ER-associated degradation (ERAD), as in Gaucher disease (GD). GD is a genetic, autosomal recessive disease that results from mutations in the GBA1 gene, encoding the lysosomal enzyme acid β-glucocerebrosidase (GCase). We have shown that mutant GCase variants undergo ERAD, the degree of which is a major determinant of disease severity. Most ERAD substrates undergo polyubiquitination and proteasomal degradation. Therefore, one expects that mutant GCase variants are substrates for several E3 ubiquitin ligases in different cells. We tested the possibility that ITCH, a known E3 ubiquitin ligase, with a pivotal role in proliferation and differentiation of the skin, recognizes mutant GCase variants and mediates their polyubiquitination and degradation. Our results strongly suggest that ITCH interacts with mutant GCase variants and mediates their lysine 48 polyubiquitination and degradation.
UR - http://www.scopus.com/inward/record.url?scp=84875249831&partnerID=8YFLogxK
U2 - 10.1093/hmg/dds535
DO - 10.1093/hmg/dds535
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AN - SCOPUS:84875249831
SN - 0964-6906
VL - 22
SP - 1316
EP - 1327
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 7
M1 - dds535
ER -