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.