Endogenous association of Bim BH3‐only protein with Mcl‐1, Bcl‐xL and Bcl‐2 on mitochondria in human B cells

Open Access
Publisher Website
Google Scholar
Abstract
Bim is an essential regulator of lymphoid system homeostasis and appears essential for B cell apoptosis induction. The mechanism by which Bim isoforms are held in an inactive form remains poorly documented in normal B cells. In the current study, we demonstrated that in normal tonsil B cells the three major Bim isoforms are strongly associated with the anti‐apoptotic Bcl‐2 family members Mcl‐1, Bcl‐2 and Bcl‐xL. On the other hand, only a weak association of BimEL and L with the dynein LC8 chain has been found. In addition, there is no free Bim in normal B cells. Moreover, subcellular fractionation demonstrated that Bim and the anti‐apoptotic counterparts are localized preferentially in the mitochondria‐rich fraction. The fact that most Bim was found in this fraction supports the hypothesis that it is sequestered by anti‐apoptotic molecules in mitochondria where its pro‐apoptotic activity is controlled. Of interest, BimS is essentially complexed to Mcl‐1 and the Mcl‐1/Bim complex is the most abundant among the three types of complexes. This supports the idea that this complex is critical for the control of B cell death. In conclusion, these results favor a model in which Bim release from anti‐apoptotic proteins is a critical event for initiation of apoptosis.