BH3‐ligand regulates access of MCL‐1 to its E3 ligase

Abstract

A genome wide search for new BH3‐containing Bcl‐2 family members was conducted using position weight matrices (PWM) and identified a large (480 kDa), novel BH3‐only protein, originally called LASU1 (now also known as Ureb‐1, E3^histone, ARF‐BP1, and Mule). We demonstrated that LASU1 is an E3 ligase that ubiquitinated Mcl‐1 in vitro and was required for its proteasome‐dependent degradation in HeLa cells. Of note, the BH3 domain of LASU1 interacted with Mcl‐1 but not with Bcl‐2 or Bcl‐Xl. A competing BH3‐ligand derived from Bim interacted with Mcl‐1 and prevented its interaction with LASU1 in HeLa cells, causing elevation of the steady‐state levels of Mcl‐1. This suggests that the unliganded form of Mcl‐1 is sensitive to LASU1‐mediated degradation of Mcl‐1.