Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling

Nobuhiko Kayagaki, Christopher C. Goodnow& Vishva M. Dixit

Nature 526, 666–671 (29 October 2015)

Speaker: Yeh, Zheng-Wei (葉正偉)                              Time: 14:10~15:00, Jun. 01, 2016

Commentator: Pei-Jane Tsai, PhD (蔡佩珍 老師)      Place: Room 601

Abstract:

Lipopolysaccharide LPS used to be regarded that it only binds with surface TLR4 and triggers immune response. Further studies showed that intracelluar LPS can also trigger immune response by non-canonical inflammasome signalling. Caspase-11 is a kind of non-canonical inflammasome that can directly bind with intracellular LPS and be activated. Activated LPS can trigger NLRP3- and ASC- dependent activation of caspase-1, then produce mature IL-1β, induce pyroptosis and cause septic shock. However, we still don't understand precisely how caspase-11 trigger downstream non-canonical inflammasome signalling. In this study, authors used ENU-mutagenized mice and found that gasdermin D is involved in LPS-induced IL-1β and caspase-1 maturation. Author further investigated the role of gasdermin D in non-canonical signalling with BMDM from Gsdmd knockout mice. Results showed that gasdermin D is an essential substrate for caspase-11, and p30 fragment executes triggering downstream signalling. In macrophages from Gsdmd knockout mice, they expressed defective pyroptosis and IL-1β secretion under LPS stimulation. In vivo test also show that knockout mice were protected from lethal sepsis. Authors will further study on how gasdermin D active fragment activated downstream non-canonical signalling.

Reference:

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