期刊
BIOCHEMICAL JOURNAL
卷 473, 期 -, 页码 899-910出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20151077
关键词
ADP-ribosylation; gene regulation; liver X receptor; nuclear receptor; post-translational modification; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase
资金
- Canadian Institutes of Health Research [MOP-494265, MOP-125919]
- Ontario Graduate Student Stipend Program
- Canadian Institutes of Health Research New Investigator Award
- Ontario Ministry of Innovation [ER10-07-028]
- University of Oslo
- Johan Throne Holst Foundation
- Novo Nordic Foundation
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 alpha (LXR alpha) and LXR beta 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(-/-) mous 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 LXR alpha/beta 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 LXR alpha or LXR beta co-localized in the nucleus. In vitro ribosylation assays provided evidence that TIPARP mono-ADP-ribosylated both LXR alpha and LXR beta. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据