Coronavirus: Hungary Confirmed Cases Reach 343, Another Elderly Patient Dead

https://www.ncbi.nlm.nih.gov/pubmed/30143555

2018 Aug 24;3(26). pii: eaar6689. doi: 10.1126/sciimmunol.aar6689.

Gasdermin D plays a vital role in the generation of neutrophil extracellular traps.

Abstract

The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.

https://doi.org/10.1016/j.str.2018.03.002. SUMMARY. Pyroptosis is an inflammatory form of programmed cell death 

   Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition

Graphical Abstract

AuthorsZhonghua Liu, Chuanping Wang,Joseph K. Rathkey, Jie Yang,George R. Dubyak, Derek W. Abbott,Tsan Sam Xiao

The gasdermin family members are dangerous molecules capable of forming membrane pores that induce cytolysis, and thus may have evolved autoinhibition mechanisms that regulate cell death through their C-terminal domains.It remains to be determined how most of the gasdermin family members are maintained in their autoinhibited states and how they are activated through protease cleavage or other post-translational modifications, and ultimately how they function under physiological and pathological conditions. Understanding the molecular mechanisms of gasdermin transformation from soluble proteins to transmembrane pores will provide valuable insights into the roles of pyroptosis in immune protection against infections and in inflammatory disorders. These will pave the way for therapeutic targeting of various inflammatory disorders such as sepsis (Jo-gensen and Miao,2015), multiple sclerosis (Guoetal.,2015;Martinet al., 2016), and inflammatory bowel disease (Zaki et al., 2011).

…our data are consistent with the idea that the GSDMD-C domain serves important functioning suppressing cell death by the GSDMD-N domain, and that reduced autoinhibition may promote the assembly of membrane pores by GSDMD-N and spontaneous cell death.

 

 

 

 

 

 

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