Caspase is a family of protease that plays an important role in programmed cell death. Specifically, caspase also has other definite roles in programmed cell death, such as apoptosis and necrotic necrosis of coke cells. Besides, caspase also plays a role in inflammation, so it directly deals with proinflammatory cytokines such as IL-1 β. Moreover, the caspase cascade system plays an important role in the induction, transduction, and amplification of apoptosis signals. Caspase, which is closely related to apoptosis, is an aspartate specific cysteine protease and a member of the interleukin-1 β converting enzyme family. Furthermore, caspase also has other definite functions, such as tumor suppression, cell proliferation, cell differentiation, neurodevelopment, and axon guidance. Inflammatory corpuscles are signal transduction platforms that promote the activation of inflammatory caspases such as caspases-1, – 4, – 5, and – 11. Ac-FLTD-CMK, a gasdermin D (GSDMD)-derived inhibitor, is a specific inflammatory caspases inhibitor.
Ac-FLTD-CMK is a specific inflammatory caspases inhibitor.
But, how does Ac-FLTD-CMK protect against inflammatory cells via caspases? Let’s discuss it in detail. In the beginning, Ac-FLTD-CMK, a gasdermin D (GSDMD)-derived inhibitor, is a specific inflammatory caspases inhibitor. Meanwhile, Ac-FLTD-CMK inhibits caspases-1 (IC50 of 46.7 nM), caspases-4 (IC50 of 1.49 μM), caspases-5 (IC50 of 329 nM), and caspases-11, but not the apoptotic caspases such as caspase-3.
In the second place, Ac-FLTD-CMK inhibits GSDMD cleavage by caspases-1, -4, -5, and -11 in vitro. Nonetheless, Ac-FLTD-CMK suppresses pyroptosis downstream of both canonical and noncanonical inflammasomes. Importantly, Ac-FLTD-CMK reduces IL-1β release following activation of the NLRP3 inflammasome in macrophages. By contrast, Ac-FLTD-CMK does not target caspase-3 or apoptotic cell death. Particularly, the crystal structure of caspase-1 in complex with Ac-FLTD-CMK reveals extensive enzyme-inhibitor interactions involving both hydrogen bonds and hydrophobic contacts.
All in all, Ac-FLTD-CMK is a specific inflammatory caspases inhibitor.
References:
Jie Yang, et al. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6792-6797.