Pore formation by GSDMD is the effector mechanism of pyroptosis

Abstract

Pyroptosis is a unique, pro‐inflammatory form of lytic cell death that is initiated by the activation of inflammatory caspases. The caspase substrate gasdermin D (GSDMD) plays a critical function in pyroptosis, yet the precise mode of action of this molecule in cell death execution remained unclear. Several recent reports, including a The EMBO Journal article, show that the caspase‐matured N‐terminal fragment of GSDMD is recruited to lipid membranes to form pore‐like structures, which constitutes the key effector mechanism of pyroptotic cell death.

Figure 1. GSDMD‐mediated pore formation induces pyroptotic cell death

Upon activation, inflammatory caspases cleave cytosolic GSDMD to release the auto‐inhibition of the C‐terminal part. The cleaved N‐terminal fragment translocates to the plasma membrane to bind phospholipids of the inner leaflet presumably utilizing the conserved RKRR motif. At the same time, cardiolipin binding may enable recruitment of N‐terminal GSDMD to mitochondria. Pore assembly at the plasma membrane enables breakdown of ion gradients and efflux of cytosolic proteins that are small enough to pass through the pores. Subsequently, water influx driven by oncotic pressure induces cell swelling and rupture of the plasma membrane, which releases the cytosolic content. Released N‐terminal GSDMD may exhibit extracellular in trans bactericidal activity. Of note, occurrence of phospholipids at the plasma membrane does not represent the actual quantitative distribution.