title: TCDD-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) mono-ADP-ribosylates and co-activates liver X receptors.
abstract: Members of the poly-ADP-ribose polymerase (PARP) family catalyse the ADP-ribosylation of target proteins and are known to play important roles in many cellular processes, including DNA repair, differentiation and transcription. The majority of PARPs exhibit mono-ADP-ribosyltransferase activity rather than PARP activity; however, little is known about their biological activity. In the present study, we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP), mono-ADP-ribosylates and positively regulates liver X receptor α (LXRα) and LXRβ activity. Overexpression of TIPARP enhanced LXR-reporter gene activity. TIPARP knockdown or deletion reduced LXR regulated target gene expression levels in HepG2 cells and in Tiparp(-/-)mouse embryonic fibroblasts (MEFs) respectively. Deletion and mutagenesis studies showed that TIPARP's zinc-finger and catalytic domains were required to enhance LXR activity. Protein interaction studies using TIPARP and LXRα/β peptide arrays revealed that LXRs interacted with an N-terminal sequence (a.a. 209-236) of TIPARP, which also overlapped with a putative co-activator domain of TIPARP (a.a. 200-225). Immunofluorescence studies showed that TIPARP and LXRα or LXRβ co-localized in the nucleus.In vitroribosylation assays provided evidence that TIPARP mono-ADP-ribosylated both LXRα and LXRβ. Co-immunoprecipitation (co-IP) studies revealed that ADP-ribosylase macrodomain 1 (MACROD1), but not MACROD2, interacted with LXRs in a TIPARP-dependent manner. This was complemented by reporter gene studies showing that MACROD1, but not MACROD2, prevented the TIPARP-dependent increase in LXR activity. GW3965-dependent increases in hepatic Srebp1 mRNA and protein expression levels were reduced in Tiparp(-/-)mice compared with Tiparp(+/+)mice. Taken together, these data identify a new mechanism of LXR regulation that involves TIPARP, ADP-ribosylation and MACROD1.
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1046 Blindern, 0317 Oslo, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Bindesbøll
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Susanna
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: Bott
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cho
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: MacPherson
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1046 Blindern, 0317 Oslo, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Grønning-Wang
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1046 Blindern, 0317 Oslo, Norway.
authors.forename: Hilde Irene
authors.initials: HI
authors.lastname: Nebb
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 1046 Blindern, 0317 Oslo, Norway Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada jason.matthews@medisin.uio.no.
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D033703:Nucleoside Transport Proteins; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; C523332:MACROD2 protein, human; C523333:Macrod2 protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D033703:Nucleoside Transport Proteins; D057093:Orphan Nuclear Receptors; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C579717:TiPARP protein, human; D000246:Adenosine Diphosphate Ribose; D036002:ADP Ribose Transferases; C000592801:Parp7 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D006867:Hydrolases; D045643:DNA Repair Enzymes
keywords: 2; 3; 7; 8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase; ADP-ribosylation; gene regulation; liver X receptor; nuclear receptor; post-translational modification