To clarify the role of E3 ligase that is involved in ER stress signaling, we attempted to find its substrate. In this study, we succeeded in identifying an Aβ degrading enzymes (proteases). The substrate protein was polyubiquitinated but not degraded by proteasome. Next, we examined if ubiquitination results in the change in the enzymatic activity. Hydrolysis of Aβ peptide was significantly suppressed by this modification. Therefore, it is suggested that under the endoplasmic reticulum stress environment, an E3 ligases is highly expressed, and ubiquitination of the substrate may alter intracellular localization by regulating the enzyme activity.