Abstract
Pyroptosis is lytic, programmed cell death and plays a critical role against microbial invasion, functioning as an innate immune effector mechanism. The pore-forming protein gasdermin D (GSDMD), a member of gasdermin family proteins, is a primary effector of pyroptosis. The cleavage of inflammasome-associated inflammatory caspases activates GSDMD to liberate the N-terminal effector domain from the C-terminal inhibitory domain and form pores in the cellular plasma membrane. Emerging evidence shows that the pore-forming activity of GSDMD beyond pyroptosis and modifies non-lytic cytosolic protein secretion in living cells and innate immunity. While the essential roles of GSDMD in bacterial infection and cancer have been widely investigated, the importance of GSDMD in virus infection, including coronaviruses, remains elusive. Here, we review the current literature regarding the activation and functions of GSDMD during virus infections. Last, we further discuss the roles of GSDMD and the therapeutic potential of targeting this GSDMD pore-forming activity in coronavirus diseases.
Highlights
Pyroptosis, one of the types of programmed cell deaths (Pyroptosis, apoptosis, necroptosis), functions as the critical innate effector of host responses in microbial infection and cancer and has attracted considerable attention in recent years (Aglietti et al, 2016; Frank and Vince, 2019)
It has long been believed that the secretion of inflammatory cytokine in the non-canonical pyroptosis pathway depends on the cleavage of Gasdermin D (GSDMD), which forms pores in cytomembrane to allow K+ efflux to active NLRP3 inflammasome and promotes the secretion of IL-1β (Kayagaki et al, 2011; Rühl and Broz, 2015)
Norovirus infection of STAT1-deficient mice can activate canonical NLRP3 inflammasome and lead to the maturation of IL-1β and GSDMD-dependent pyroptosis, which contributes to immunopathology during gastrointestinal norovirus infection (Dubois et al, 2019)
Summary
Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China. Reviewed by: Thomas Dong, University of Texas Southwestern Medical Center, United States. Pyroptosis is lytic, programmed cell death and plays a critical role against microbial invasion, functioning as an innate immune effector mechanism. The pore-forming protein gasdermin D (GSDMD), a member of gasdermin family proteins, is a primary effector of pyroptosis. The cleavage of inflammasome-associated inflammatory caspases activates GSDMD to liberate the N-terminal effector domain from the C-terminal inhibitory domain and form pores in the cellular plasma membrane. Emerging evidence shows that the pore-forming activity of GSDMD beyond pyroptosis and modifies non-lytic cytosolic protein secretion in living cells and innate immunity. We review the current literature regarding the activation and functions of GSDMD during virus infections. We further discuss the roles of GSDMD and the therapeutic potential of targeting this GSDMD pore-forming activity in coronavirus diseases
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