The formation of pores by a particular protein, gasdermin D, plays a key role in inflammatory reactions. During its activation, an inhibitory part is split off. More than 30 of the remaining protein fragments then combine to form large pores in the cell membrane, which allow the release of inflammatory messengers.
As methods for studying these processes in living cells have so far been inadequate, the sequence of oligomerization, pore formation and membrane incorporation has remained unclear. An international research team led by the University Hospital Bonn (UKB) and the University of Bonn has succeeded in answering this question with the help of antibody fragments, so-called nanobodies, which they have identified. They hope that this will lead to potential therapeutic applications.
Their results have now been published in Nature Communications . Inflammasomes, large multiprotein complexes of the innate immune system, activate and control inflammatory reactions in our body. An important step in the signaling cascade triggered by them is the cleavage of the protein gasdermin D (GSDMD).
The active part of GSDMD, the so-called N-terminal domain (NTD), can then form pores in cellular membranes, which on the one hand enable the release of pro-inflammatory cytokines and on the other hand trigger pyroptosis—a form of cell death that further fuels inflammation. "But how exactly and where GSDMD assembles into pores, and whether this step can be inhibited, was previously unclear," s.
