Abstract
Apoptosis is a form of programmed cell death in multicellular organisms. Bcl-2 prevents apoptosis and promotes cellular survival by neutralizing BH3 domain-containing proteins, which directly activate the pore-forming proteins BAX and BAK. However, Bcl-2 is not known to regulate other cell death effectors such as gasdermin D (GSDMD) or mixed lineage kinase domain-like (MLKL), whose activation causes pyroptosis and necroptosis, respectively. Here, we identify a BH3-like domain in both GSDMD and MLKL that mediates an interaction with B-cell lymphoma 2 (Bcl-2). The presence of Bcl-2 reduced GSDMD cleavage at D275 by caspase-1, 4 or 5, and enhanced the GSDMD cleavage at D87. The GSDMD D87 cleavage inactivates the pyroptotic execution program. The presence of Bcl-2 also limited RIP3 mediated phosphorylation of MLKL, which reduced MLKL oligomerization and tempered the induction of necroptosis. Our observations suggest that the presence of Bcl-2 limits the induction of three forms of cell death apoptosis, pyroptosis, and necroptosis.
Highlights
Apoptosis helps preserve tissue homeostasis and is obligatory for normal embryonic development[1]
To address whether B-cell lymphoma 2 (Bcl-2) might have a similar role in the regulation of pyroptosis, we carefully examined the amino acid sequence of pyroptotic executor protein gasdermin D (GSDMD) for the presence of a BH3-like domain
To verify that this region might confer upon GSDMD the ability to interact with Bcl-2, we checked whether the endogenous proteins coimmunoprecipitated using lysates prepared from the human macrophage cell line THP-1
Summary
Apoptosis helps preserve tissue homeostasis and is obligatory for normal embryonic development[1]. The intrinsic pathway known as the mitochondrial apoptotic pathway is tightly regulated by members of the Bcl-2 protein family. Together these protein function to modulate the permeability of the mitochondrial outer membrane[3]. Based on their operational roles in apoptosis and the number of Bcl-2 homology (BH) domains that they possess, the Bcl-2 family members are divided into three subgroups[4]. One subgroup includes the proapoptotic members of the family such as Bax and Bak. One subgroup includes the proapoptotic members of the family such as Bax and Bak These proteins mediate the increased mitochondrial outer membrane permeability.
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