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. 2021 Aug 27;29(1):230–245. doi: 10.1038/s41418-021-00853-5

Fig. 8. KIRA6 curtails the inflammatory traits of immunogenic treatments.

Fig. 8

Chemotherapy with mitoxantrone or Hypericin-mediated photodynamic therapy (Hyp-PDT) (illustrated by the light as essential triggering factor) induces loss of ER homeostasis, which leads in case of the most pronounced ER stress inducer Hyp-PDT to maladaptive UPR and immunogenic cell death. Both immunogenic treatments, however, also elicit an early stress response, which is independent of the UPR/ISR and caspase-mediated cell death. This premortem stress response leads to the production of a common subset of proinflammatory chemokines through ROS and Ca2+-mediated activation of the NF-κB and AP-1 transcriptional program. KIRA6, an inhibitor of the IRE1α kinase activity, blunts the inflammatory output of immunogenic therapies in an IRE1α-independent manner. One of the off-target effectors of KIRA6 is the cytosolic HSP60, which is required for the full activation of NF-κB/AP-1 and CXCL8 production by immunogenic treatments.