The Fusion Oncoprotein PML-RARα Induces Endoplasmic Reticulum (ER)-associated Degradation of N-CoR and ER Stress

Abstract

PML-RARα, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-α (RARα), causes acute promyelocytic leukemias (APL). Although the role of nuclear PML-RARα has been extensively studied, a significant amount of PML-RARα is in the cytoplasm. The role cytoplasmic PML-RARα plays in leukemogenesis is unknown. Here we report that PML-RARα induces the N-CoR accumulation in the endoplasmic reticulum (ER), leading to the induction of ER stress and the processing of activating transcription factor 6 (ATF6), the unfolded protein response. PML-RARα stimulates the ubiquitylation of N-CoR via Ubc6 that is involved in the protein quality control. This ER-associated degradation (ERAD) of N-CoR reduces the soluble N-CoR protein levels in the nucleus. The two N-CoR-interacting sites in PML-RARα are required for the ERAD of N-CoR, suggesting the aberrant binding of PML-RARα to N-CoR may induce the ERAD of N-CoR. Overexpression of N-CoR induces the differentiation of APL-derived NB4 cells, suggesting that the low levels of N-CoR in the nucleus may contribute at least partly to PML-RARα-mediated leukemogenesis.