Extracellular Poly(ADP-Ribose) Is a Pro-inflammatory Signal for Macrophages

Krukenberg, Kristin A.; Kim, Sujeong; Tan, Edwin S.; Maliga, Zoltan; Mitchison, Timothy J.

doi:10.1016/j.chembiol.2015.03.007

Cited by 42 publications

(40 citation statements)

References 31 publications

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“…Our biochemical data suggest that ENPP1 may be involved in the metabolism of extracellular PAR through its hydrolysis and release of phosphoribosylated proteins, PRAMP and, contextually, free PAR – a molecule that has previously been described as an extracellular stimulus driving inflammatory signalling . Moreover, colocalization of ARTCs and ENPP1 on the extracellular membrane may suggest a physiological function for ENPP1 in the regulation of immune cell activity and survival.…”

Section: Discussionmentioning

confidence: 59%

ENPP1 processes protein ADP‐ribosylation in vitro

et al. 2016

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ADP‐ribosylation is a conserved post‐translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP‐ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP‐ribosylation can be reversed by the macrodomain‐containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP‐ribose as well as consecutive ADP‐ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly(ADP‐ribose) to mono(ADP‐ribose). Recently, proteins containing the NUDIX domain – namely human NUDT16 and bacterial RppH – have been shown to process in vitro protein ADP‐ribosylation through an alternative mechanism, converting it into protein‐conjugated ribose‐5′‐phosphate (R5P, also known as pR). Though this protein modification was recently identified in mammalian tissues, its physiological relevance and the mechanism of generating protein phosphoribosylation are currently unknown. Here, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as the first known mammalian enzyme lacking a NUDIX domain to generate pR from ADP‐ribose on modified proteins in vitro. Thus, our data show that at least two enzyme families – Nudix and ENPP/NPP – are able to metabolize protein‐conjugated ADP‐ribose to pR in vitro, suggesting that pR exists and may be conserved from bacteria to mammals. We also demonstrate the utility of ENPP1 for converting protein‐conjugated mono(ADP‐ribose) and poly(ADP‐ribose) into mass spectrometry‐friendly pR tags, thus facilitating the identification of ADP‐ribosylation sites.

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Section: Discussionmentioning

confidence: 59%

ENPP1 processes protein ADP‐ribosylation in vitro

et al. 2016

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“…89,90) Therefore, I would like to remind readers that PARP used in this review means PARP-1. After the completion of this overview, I happened to find the paper by Kurukenberg et al describing on the relation between innate immunity and extracellular poly(ADP-ribose) 105) which seems to be first-ever in terms of focusing on poly(ADP-ribose) alone, that is, extracellular poly(ADP-ribose). This was really like a blot from the blue.…”

Section: Discussionmentioning

confidence: 99%

Overview on poly(ADP-ribose) immuno-biomedicine and future prospects

Kanai

2016

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Poly(ADP-ribose), identified in 1966 independently by three groups Strassbourg, Kyoto and Tokyo, is synthesized by poly(ADP-ribose) polymerases (PARP) from NAD+ as a substrate in the presence of Mg2+. The structure was unique in that it has ribose-ribose linkage. In the early-1970s, however, its function in vivo/in vitro was still controversial and the antibody against it was desired to help clear its significance. Thereupon, the author tried to produce antibody against poly(ADP-ribose) in rabbits and succeeded in it for the first time in the world. Eventually, this success has led to the following two groundbreaking papers in Nature: “Naturally-occurring antibody against poly(ADP-ribose) in patients with autoimmune disease SLE”, and “Induction of anti-poly(ADP-ribose) antibody by immunization with synthetic double-stranded RNA, poly(A)·poly(U)”.On the way to the publication of the first paper, a reviewer gave me a friendly comment that there is “heteroclitic” fashion as a mechanism of the production of natural antibody. This comment was really a God-send for me, and became a train of power for publication of another paper, as described above. Accordingly, I thought this, I would say, episode is worth describing herein. Because of its importance in biomedical phenomena, a certain number of articles related to “heteroclitic” have become to be introduced in this review, although they were not always directly related to immuno-biological works on poly(ADP-ribose). Also, I tried to speculate on the future prospects of poly(ADP-ribose), product of PARP, as an immuno-regulatory molecule, including either induced or naturally-occurring antibodies, in view of “heteroclitic”.

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“…An intriguing role for extracellular PAR was identified by the group of Mitchison (161). PAR was shown to activate cytokine release by macrophages, which is associated with activation of innate immune responses.…”

Section: Parps In Proviral Responsesmentioning

confidence: 99%

“…PARP hyperactivation has been identified in several central nervous system disorders, including neuroinflammation, neurodegeneration, and ischemia. Extracellular PAR, such as could be released by necrotic cells, was identified as a damage-associated molecular pattern that stimulates inflammatory signaling (161).…”

Section: Parps In Inflammation and Immunitymentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Extracellular Poly(ADP-Ribose) Is a Pro-inflammatory Signal for Macrophages

Cited by 42 publications

References 31 publications

ENPP1 processes protein ADP‐ribosylation in vitro

ENPP1 processes protein ADP‐ribosylation in vitro

Overview on poly(ADP-ribose) immuno-biomedicine and future prospects

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

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