IFI27 and BAX are Essential for GSDME‐Mediated Myeloma Cell Pyroptosis
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
ABSTRACT Induction of pyroptosis is a novel strategy for multiple myeloma (MM) treatment, but the underlying mechanism remains elusive. In the analysis of the transcriptomic profile in pyroptotic MM cells, we find the interferon‐alpha inducible protein IFI27 is strikingly upregulated. IFI27 is downregulated in MM cells in association with poor prognosis, but its overexpression displays great potency to trigger pyroptosis in both MM cell lines and newly diagnosed MM cells in a GSDME‐dependent manner. Moreover, ectopic IFI27 impairs mitochondrial structure and function. Interestingly, when mitochondria are depleted, IFI27 almost fails to induce MM cell pyroptosis. Mechanistic studies show that IFI27 recruits N‐GSDME to mitochondria via BAX, therefore triggering pyroptosis. When IFI27 is knocked down, MM cells hardly undergo pyroptosis even when triggered by N‐GSDME, BAX, or chemotherapeutic agents. Although GSDMD induces cell pyroptosis independent of BAX, BAX is required for IFI27‐ and N‐GSDME‐induced cell pyroptosis. Lastly, ectopic IFI27 promotes GSDME activation and triggers MM cell pyroptosis in vivo and strikingly prolongs the survival of mice with MM. In summary, the present study finds that IFI27 and BAX are essential for GSDME‐mediated cell pyroptosis, and induction of IFI27 may represent a promising strategy for the treatment of MM expressing GSDME. The proposed model of GSDME‐mediated MM cell pyroptosis modulated by IFI27 and BAX. IFI27 is downregulated in MM cells.
Abstract
ABSTRACT Induction of pyroptosis is a novel strategy for multiple myeloma (MM) treatment, but the underlying mechanism remains elusive. In the analysis of the transcriptomic profile in pyroptotic MM cells, we find the interferon‐alpha inducible protein IFI27 is strikingly upregulated. IFI27 is downregulated in MM cells in association with poor prognosis, but its overexpression displays great potency to trigger pyroptosis in both MM cell lines and newly diagnosed MM cells in a GSDME‐dependent manner. Moreover, ectopic IFI27 impairs mitochondrial structure and function. Interestingly, when mitochondria are depleted, IFI27 almost fails to induce MM cell pyroptosis. Mechanistic studies show that IFI27 recruits N‐GSDME to mitochondria via BAX, therefore triggering pyroptosis. When IFI27 is knocked down, MM cells hardly undergo pyroptosis even when triggered by N‐GSDME, BAX, or chemotherapeutic agents. Although GSDMD induces cell pyroptosis independent of BAX, BAX is required for IFI27‐ and N‐GSDME‐induced cell pyroptosis. Lastly, ectopic IFI27 promotes GSDME activation and triggers MM cell pyroptosis in vivo and strikingly prolongs the survival of mice with MM. In summary, the present study finds that IFI27 and BAX are essential for GSDME‐mediated cell pyroptosis, and induction of IFI27 may represent a promising strategy for the treatment of MM expressing GSDME. The proposed model of GSDME‐mediated MM cell pyroptosis modulated by IFI27 and BAX. IFI27 is downregulated in MM cells. Upon pyroptotic stimulation, such as DOX or ETO treatment, IFI27 is induced, therefore liberating BAX from BCL‐2 ❶. BAX is then recruited to mitochondria and forms homo‐oligomeric channels in OMM, therefore leading to cytochrome C leaks to the cytosol ❷ and activating Caspase‐3 ❸, which further cleaves and activates GSDME ❹❺. The resultant N‐GSDME is further identified by BAX ❻ and is recruited to OMM by IFI27 ❼. N‐GSDME forms pores in OMM and also leads to cytochrome C release ❽, therefore further activating Caspase‐9/Caspase‐3/GSDME ❾. More N‐GSDME fragments then form pores in the plasma membrane, leading to cell pyroptosis ❿. The upregulated IFI27, liberated BAX, and activated GSDME collaborate in mitochondrial structural damage and dysfunction that further exaggerates MM cell pyroptosis. advs77164-abs-0001 graphical