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Programmed cell death serves as a critical defense mechanism during viral infection. The kinases RIPK1 and RIPK3, central regulators of programmed cell death pathways, undergo precise modulation through various post-translational modifications. The ADP-ribosylation of RIPK1/3 has been documented, but the functional consequences of this modification on kinase activity and downstream cell death signaling remain elusive.

PARP family proteins are ADP-ribosyltransferases that can modify target proteins with ADP-ribose. They have recently emerged as important regulators of antiviral immunity.

In a study in the Proceedings of the National Academy of Sciences, a research team led by Prof. Yuan Junying at the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences revealed how PARP12, a mono-ADP-ribosyltransferase, modulates cell fate decisions during viral infection.

Through systematic analysis of the mass spectrometry data, researchers identified PARP12 as a novel regulator of cell death pathways.

They demonstrated that PARP12 specifically mono-ADP-ribosylates (MARylates) RIPK1 and RIPK3, promoting RIPK1-RIPK3-dependent necroptosis while simultaneously suppressing RIPK1-caspase-8-mediated apoptosis. Besides, they found that PARP12 negatively regulates interferon-stimulated gene expression in a RIPK1-dependent manner.

The physiological relevance of these findings was confirmed in vivo using PARP12-deficient mice. Following influenza virus infection, PARP12 knockout mice exhibited significantly improved survival outcomes and attenuated weight loss compared to wild-type controls.

Moreover, histopathological examination revealed reduced pulmonary necroptosis and lower viral titers in PARP12-deficient animals, establishing PARP12 as a critical molecular switch governing cell death and immune responses during viral infection.

The findings of this study not only deepen our understanding of host-virus interactions but also suggest PARP12 as a potential therapeutic target for influenza and other viral infections.