Identifying GSDME/DFNA5 as a Multifaceted Regulator of the Apoptotic Program
Programmed cell death (PCD) pathways play critical physiological functions in directing our development, shaping our immune system, and maintaining our health, yet we still do not fully understand the molecules that control these processes. As PCD is vitally important for human health, it is not surprising that disruption of these signaling pathways can lead to disease. Having a more complete and detailed understanding of how these pathways are regulated can lead to the identification of novel drug targets, prognostic indicators, and biomarkers which can in turn improve disease prevention and treatment. Members of the gasdermin superfamily are just emerging as critical proteins involved in executing PCD, however their precise function and regulatory mechanisms are still not fully elucidated. One member, gasdermin E (GSDME), is transcriptionally suppressed in cancers and genetic mutations can cause progressive hearing loss. How the function of GSDME relates to these diseases, however, is currently unknown which limits our understanding of how to prevent or treat them. The work presented in this thesis sheds light on two novel functions of GSDME, both of which are involved in regulating one form of PCD called apoptosis. First, GSDME is a substrate of the cysteine protease caspase-3. When caspase-3 is activated during apoptosis, it cleaves GSDME between its N- and C-terminal domains liberating an N-terminal fragment (GSDME-N) that has an intrinsic ability to form pores in biomembranes. GSDME-N first forms pores in the mitochondria to potentiate the apoptotic pathway by augmenting the release of proapoptotic molecules into the cytosol. Later in the apoptotic program, GSDME-N also forms pores in the plasma membrane, which leads to lysis of the cell and the release of inflammatory molecules. Interestingly, these functions also appear to be conserved by other gasdermin family members. These discoveries may explain why certain forms of cancer need to suppress GSDME expression and how mutations in this gene can lead to hearing loss, and they also open new avenues for disease intervention.
Rogers, Corey L, "Identifying GSDME/DFNA5 as a Multifaceted Regulator of the Apoptotic Program" (2019). ETD Collection for Thomas Jefferson University. AAI13881747.