Related Experiment Video
Updated: Sep 19, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis
Xin Huang1,2,3, Fangxia Li2,4, Lin Liu1,2,3
1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNFα may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFNγ and TNFα. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.
Insights
Poly(ADP-ribose) polymerase 12 (PARP12) regulates cell death pathways by modifying RIPK1 and RIPK3. PARP12 deficiency promotes antiviral responses and reduces necroptosis.
Area of Science:
- Cellular biology
- Immunology
- Molecular mechanisms of cell death
Background:
- Necroptosis and apoptosis are distinct cell death pathways.
- Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of both pathways.
- Post-translational modifications of RIPK1 control its activity and complex formation.
Purpose of the Study:
- To investigate the role of Poly(ADP-ribose) polymerase 12 (PARP12) in regulating RIPK1 and RIPK3.
- To elucidate the mechanism by which PARP12 influences necroptosis and apoptosis.
- To determine PARP12's impact on cellular antiviral responses.
Main Methods:
- Investigated PARP12 interaction with RIPK1 and RIPK3 in cells stimulated with IFNγ and TNFα.
- Analyzed the effect of PARP12 deficiency on RIPK1 kinase activation, RIPK1/RIPK3 complex formation, and RIPK1/caspase-8 binding.
- Assessed the impact of PARP12 deficiency on interferon-stimulated genes (ISGs) and influenza A virus infection in mice.
Main Results:
- PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 and RIPK3.
- PARP12 deficiency inhibits RIPK1 kinase activation and RIPK1/RIPK3 interaction, reducing necroptosis.
- PARP12 deficiency enhances RIPK1/caspase-8 binding, sensitizing cells to apoptosis, and promotes ISG expression, conferring protection against influenza A virus.
Conclusions:
- PARP12 acts as a cellular checkpoint, modulating RIPK1 activity to promote necroptosis and inhibit apoptosis upon IFN induction.
- PARP12 is an important regulator of the cellular antiviral response.
- PARP12 deficiency confers protection against viral infections.
More Related Videos
09:15Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells
Published on: October 20, 2022
08:55Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Related Concept Videos
01:31Regulation of the Unfolded Protein Response
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
01:22PI3K/mTOR/AKT Signaling Pathway
01:31The Intrinsic Apoptotic Pathway
01:17The Extrinsic Apoptotic Pathway