Mcl-1 Reduction Due to Caspase-dependent Cleavage during Endoplasmic Reticulum Stress-induced Apoptosis

Morishima et al. (1) demonstrated that Mcl-1 is decreased by ATF6-mediated apoptosis. However, we consider that some statements could be overinterpreted. We wish to raise some important points regarding the conclusions of this work.

Caspase-dependent cleavage of Mcl-1 is a general mechanism during apoptosis. Mcl-1 cleavage occurs after Asp-127 and Asp-157 and generates four fragments of 24, 19, 17, and 12 kDa (2). The data presented by the authors clearly show the involvement of caspase-3/9/12 activation during ATF6-mediated apoptosis. However, caspase activation has not been linked to the down-regulation of Mcl-1.

As a transcription factor, the roles of ATF6 may be mediated by transcriptional regulation of downstream genes. Growing evidence shows that pro-apoptotic BH3 proteins, e.g. Noxa and Bim, can be transcriptionally up-regulated by endoplasmic reticulum stress (3, 4).

In melanoma cells, ATF6 has been demonstrated to be involved in up-regulation of Mcl-1 (5). In multiple myeloma cells, we further proved that both ATF4 and ATF6 are involved in the transcriptional up-regulation of Mcl-1 by bortezomib (unpublished data). In this regard, the authors also demonstrated that active ATF6 cannot down-regulate Mcl-1 expression at the transcriptional level.

In conclusion, it seems very likely that caspase-mediated cleavage of Mcl-1 is the major reason for Mcl-1 reduction in myoblast cells. At the transcriptional level, the activation of ATF6 may increase Mcl-1 transcription. Moreover, the pro-apoptotic BH3 proteins regulated transcriptionally by ATF6 could be the important apoptotic triggers. Subsequently, caspase signaling pathways are activated, and Mcl-1 is cleaved at the post-translational level.