Cell junction disruption drives translocation of gasdermin A and gasdermin B from cytoskeleton to plasma membrane during acantholysis

Abstract

Gasdermins (GSDMs) are a family of pore forming protein that trigger pyroptosis by permeabilizing cell membranes. Pyroptotic cells often release the proinflammatory cytokines interleukin-1{beta} (IL-1{beta}), and IL-18, thereby promoting an inflammatory response. GSDMs are typically cleaved by caspases or granzymes, which enable their translocation to the membrane. Here, we showed GSDMA and GSMDB localize to the cytoskeletal fraction of keratinocytes. Disruption of cell junctions causes gasdermin A and B (GSDMA and GSDMB) to translocate to the membrane fraction in the absence of cleavage. Cell junction disrupted keratinocytes release post-translationally modified keratins, but not IL-1{beta} or IL-18. These events depend on endocytic mechanisms associated with recycling of cell junctional proteins. Our study suggests that cell junction disruption can drive translocation of GSDMA and GSDMB from cytoskeleton to plasma membrane in keratinocytes, however there may be a subsequent trigger that causes the conformational change allowing these gasdermins to form open pores.