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.

(ADP-ribosyl)hydrolases: structure, function, and biology

“…MacroD1 stimulates the activity of NF-κB through the interaction with p65 and UXT, a transcription factor coregulator (Wu et al 2011(Wu et al , 2015. In hepatocytes, MacroD1 interacts and regulates liver X receptors α and β when these are MARylated by PARP7 (Bindesbøll et al 2016). Furthermore, MacroD1 was also proposed to act as a negative regulator of the insulin signaling pathway through the down-regulation of the insulin receptor substrate protein-1 (IRS-1) (Zang et al 2013).…”

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

“…Additionally, PARP7 has been shown to structurally modify and coactivate liver X receptors ␣ and ␤, which are important regulators in lipid and glucose metabolism, as well as inflammatory pathways. This has established the protein's function as a regulator of nuclear transcription factors (98,99). Similarly, PARP10 and PARP14 both function as regulators of gene transcription (100)(101)(102)(103).…”

Detection of piRNAs in whitespotted bamboo shark liver

“…Based on the GO annotations and definitions of the 18 identified target genes, we analyzed the potential functions of these five piRNAs. The PARP7 gene can activate liver X receptors, a kind of nuclear receptor which can affect the expression of some inflammatory mediators such as IL-6, IL-1β (Bindesboll et al, 2016). So pi-33352 may be involved in the regulation immunity during liver regeneration process.…”