PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

Đukić, Nina; Strømland, Øyvind; Elsborg, Jonas Damgaard; Munnur, Deeksha; Zhu, Kang; Schuller, Marion; Chatrin, Chatrin; Kar, Pulak; Duma, Lena; Suyari, Osamu; Rack, Johannes Gregor Matthias; Baretić, Domagoj; Crudgington, Dorian Richard Kenneth; Groslambert, Joséphine; Fowler, Gerissa; Wijngaarden, Sven; Prokhorova, Evgeniia; Rehwinkel, Jan; Schüler, Herwig; Filippov, Dmitri V.; Sanyal, Sumana; Ahel, Dragana; Nielsen, Michael L; Smith, Rebecca; Ahel, Ivan

doi:10.1126/sciadv.adi2687

Cited by 28 publications

(58 citation statements)

References 93 publications

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“…Compounds that target the NAD+ binding pocket with subsequent ART activity inhibition, e.g., 14,29 , or that target the NAD+ binding pocket with subsequent Parp14 proteolysis (proteolysis targeting chimera) 30 have been reported. Also, one line of research has focused on compounds that target the Parp14 macrodomains, e.g., [31][32][33] , involved in the binding of Parp14 to ADP-ribose conjugates and removal of them 5,6 . Therefore, pharmaceutical perturbation of Parp14 functions is being explored at multiple levels from the overall Parp14 amount to its ART activity, and from Parp14-mediated ADP-ribose-dependent molecular scaffolding to reversal of ADP-ribosylation dependent cell signalling events.…”

Section: Discussionmentioning

confidence: 99%

“…The pcDNA3.1-Flag-Parp14 plasmid to express human Parp14 (N-terminal Flag-tag) has previously been described 38 . HEK293T cells grown in DMEM (21969035, Thermo Fisher) + 10% FBS (S181B-500, Biowest) + 2mM L-glutamine (25030081, Gibco) + 25mM HEPES (15630-056, Gibco) were seeded in 10 mL volumes in 10 cm dishes (1×10 6 cells / 10 cm dish) in the late afternoon. The next morning fresh media was exchanged and the cells were transfected with 4 µg of plasmid DNA using calcium-phosphate transfection reagents (prepared in-house).…”

Section: Methodsmentioning

confidence: 99%

“…Parp family members catalyze ADP-ribosylation of macromolecules, i.e., proteins and nucleic acids, which refers to the covalent conjugation of an ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD+) onto the substrate with simultaneous release of nicotinamide 4 . Parp functions that are independent of the ADP-ribosyltransferase (ART) activity such as scaffolding and modification reversal are also important, as exemplified by the recent work on ADP-ribose binding and ADPribose hydrolysis activities of Parp14 macrodomains 5,6 . Parp14 was identified as a Stat6 interacting protein 7 , and accordingly acts as a transcriptional co-factor in interleukin-4 (IL-4)-induced Stat6dependent gene expression in B cells [7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

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Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

Preprint

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Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, using a biobank IBD patient cohort as well as two mouse models of colitis, i.e., the IBD-mimicking oral dextran sulfate sodium (DSS) exposure model, and the oral Salmonella exposure model. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both colitis models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis. The Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not affect the mouse colon bacterial microbiota based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice were normal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection responses both prior and after the 1-week DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

Preprint

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“…The subfamily of macrodomain containing PARP enzymes (PARP9, PARP14 and PARP15) was originally identified as B-aggressive lymphoma (BAL) proteins 1-3 [11]. PARP9 and PARP14 contain a macrodomain with ADP-ribosyl glycohydrolase activity [12][13][14] as well as one and two ADP-ribosyl binding macrodomains, respectively [15][16][17]. PARP15, the third member of the subfamily, originated by partial duplication of the structurally more complex PARP14 early during mammalian evolution.…”

Section: Introductionmentioning

confidence: 99%

Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15

Ebenwaldner,

García Saura,

Ekström

et al. 2024

Preprint

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PARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship with PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization to stress granules point to functions in the regulation of translation. As many other PARP family members, PARP15 will readily automodify in vitro. PARP15 also contains two macrodomains predicted to bind ADP-ribosyl on targets. We used biochemical and biophysical analysis to study how the ADP-ribosyltransferase activity of PARP15 is regulated. Here we show that the catalytic domain of PARP15 dimerizes with mid-nanomolar affinity, forming the same dimer interface in solution that had already been captured by X-ray crystallography of the domain. Furthermore, we show that the formation of dimers is a prerequisite for catalytic activity and that monomeric mutant variants of the domain were catalytically inactive. Our findings suggest a regulatory mechanism by which dimerization activates either target engagement or placement of a catalytic residue, rather than NAD+ co-substrate binding, and by which the two protomers of the dimer operate independent of one another. Together, our results uncover a novel mechanism of regulation in a PARP family enzyme, which might inspire new avenues of pharmacological intervention.

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“…PARP14 is a multidomain protein and its domain architecture was recently re-analyzed using Alphafold2 (10). This analysis determined that PARP14 contains 3 RRM domains, 7 full KH domains and 1 split KH domain that are suspected to bind to nucleic acids, 3 macrodomains (MDs) one of which has an ADP-ribose hydrolase activity (MD1) (10–12), a WWE domain that is suspected to bind ADP-ribose subunits, and the ART catalytic domain (10).…”

Section: Introductionmentioning

confidence: 99%

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses

Parthasarathy,

Saenjamsai,

Hao

et al. 2024

Preprint

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PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C), however, whether it has direct antiviral function remains unclear. Here we demonstrate that the catalytic activity of PARP14 enhances IFN-I and IFN-III responses and restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14 antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1) and several negative-sense RNA viruses, including vesicular stomatitis virus (VSV), Ebola virus (EBOV), and Nipah virus (NiV), to infect A549 PARP14 knockout (KO) cells. HSV-1 had increased replication in PARP14 KO cells, indicating that PARP14 restricts HSV-1 replication. In contrast, PARP14 was critical for the efficient infection of VSV, EBOV, and NiV, with EBOV infectivity at less than 1% of WT cells. A PARP14 active site inhibitor had no impact on HSV-1 or EBOV infection, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both pro- and anti-viral functions targeting multiple viruses.

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PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

Cited by 28 publications

References 93 publications

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses

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