Glab et al.1 examined in a recent paper apoptosis induced by some drivers of endoplasmic reticulum (ER) stress. They conclude that in contrast to a previously published report,2 DR5/TRAIL-R2 and caspase-8 are universally dispensable in ER-stress-induced apoptosis. We argue here that their own data and other published reports indicate that in many models, DR5 and/or caspase-8 are essential players in apoptosis mediated by the unfolded protein response (UPR), upon chronic ER stress.

The authors analyze the effects of knocking down caspase-8, DR5, Bim and Bid. The authors describe that Bim is not essential at least in one of their three models. In line with these results, we and other authors have shown that Bim is dispensable for apoptosis mediated by the UPR in some systems even though the protein is induced; in these cases, the apoptotic cell death can be attributed to Noxa or to Caspase-8 (see Table 1 in Iurlaro et al.3 and refs. 4, 5, 6). We find inconsistent that the title and abstract mention that caspase-8 and DR5 are dispensable in ER-stress-induced apoptosis, but not that Bim is not required in their system, in contrast to earlier findings.7

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