Abstract
Caspase-mediated cleavage of the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP1) is a hallmark of apoptosis. However, it remains unclear whether PARP1 is processed during pyroptosis, a specialized cell-death program that occurs upon activation of caspase-1 in inflammasome complexes. In this article, we show that activation of the Nlrp3 and Nlrc4 inflammasomes induces processing of full-length PARP1 into a fragment of 89 kDa in a stimulus-dependent manner. Macrophages deficient for caspase-1 and those lacking the inflammasome adaptors Nlrp3, Nlrc4, and ASC were highly resistant to cleavage, whereas macrophages lacking the downstream inflammasome effector caspase-7 were partially protected. A modest, but statistically significant, reduction in Nlrp3 inflammasome-induced pyroptosis was observed in PARP1 knockout macrophages. Thus, protease-mediated inactivation of PARP1 is a shared feature of apoptotic, necrotic, and pyroptotic cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins / deficiency
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / physiology*
-
Calcium-Binding Proteins / deficiency
-
Calcium-Binding Proteins / genetics
-
Calcium-Binding Proteins / physiology*
-
Carrier Proteins / genetics
-
Carrier Proteins / physiology*
-
Caspase 1 / chemistry
-
Caspase 1 / physiology
-
Caspase 7 / chemistry
-
Caspase 7 / physiology
-
Cell Death / genetics
-
Cell Death / immunology
-
Cells, Cultured
-
Inflammation / enzymology
-
Inflammation / immunology*
-
Inflammation / pathology*
-
Inflammation Mediators / chemistry
-
Inflammation Mediators / physiology*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Peptide Fragments / chemistry
-
Peptide Fragments / metabolism
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerase Inhibitors*
-
Poly(ADP-ribose) Polymerases / chemistry
-
Poly(ADP-ribose) Polymerases / metabolism*
-
Protein Processing, Post-Translational / immunology
-
Substrate Specificity / immunology
Substances
-
Apoptosis Regulatory Proteins
-
Calcium-Binding Proteins
-
Carrier Proteins
-
Inflammation Mediators
-
Ipaf protein, mouse
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nlrp3 protein, mouse
-
Peptide Fragments
-
Poly(ADP-ribose) Polymerase Inhibitors
-
Parp1 protein, mouse
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases
-
Casp7 protein, mouse
-
Caspase 7
-
Caspase 1