Transcriptional and Epigenetic Regulation of Gasdermins

Gasdermins (GSDM) are a family of six homologous proteins (GSDMA to E and Pejvakin) in humans. GSDMA-E are pore-forming proteins targeting the plasma membrane to trigger a rapid cell death termed pyroptosis or bacterial membranes to promote antibacterial immune defenses. Activation of GSDM relies on a proteolytic cleavage but is highly dependent on GSDM expression levels. The different GSDM genes have tissue-specific expression pattern although metabolic, environmental signals, cell stress and numerous cytokines modulate their expression levels in tissues. Furthermore, expression of GSDM genes can be modulated by polymorphisms and have been associated with susceptibility to asthma, inflammatory bowel diseases and rhinovirus wheezing illness. Finally, the expression level of GSDMs controls the balance between apoptosis and pyroptosis affecting both the response and the toxicity to chemotactic drugs and antitumoral treatments. Numerous cancer demonstrate positive or negative modulation of GSDM expression levels correlating with distinct tumor-specific prognosis. In this review, we present the transcriptional and epigenetic mechanisms controlling GSDM levels and their functional consequences in asthma, infection, cancers and inflammatory bowel disease to highlight how this first layer of regulations has key consequences on disease susceptibility and response to treatment.