A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis

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

The authors’ own data (ref. 1, Figure 3c) indicate that Bid is crucial in one of their models: HCT116. Moreover, although the authors report a drastic reduction of apoptosis with some treatments, they also show that over 20% of Bax, Bak-deficient cells undergo apoptosis (ref. 1, Figures 2e and f). We suggest that this apoptosis is mediated by caspase-8 as described in Bax, Bak-deficient HCT116 and MEFs treated with UPR-inducing stimuli.^{4, 6} Indeed, a certain role for caspase-8 is shown by the authors in Supplementary Figure 2,¹ but this is not mentioned in the title or abstract.

Regarding the role of DR5, authors do observe reduction of cell death in one knockout clone. Importantly, the authors seem focused to disprove one study, while ignoring numerous studies that have shown a role of DR5 and caspase-8 in apoptosis activated by different UPR-inducing stimuli such as thapsigargin or glucose deprivation^{3, 8, 9} (Table 1). Moreover, it is possible that in cells knocked out for DR5, it is DR4 or other death receptors (reviewed in Iurlaro et al.³) that may be participating in caspase-8 activation and Bid cleavage, as we have recently described in ATF4-mediated cell death.⁶

Table 1 Examples of reports showing a role for caspase-8 and/or DR5 in apoptosis mediated by components of the UPR or the integrated stress response

Altogether, these data indicate that DR5, caspase-8, Bim, Bid and Noxa are required for ER stress and UPR-mediated death in a cell type-dependent manner.