Poly(ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation.
Poly(ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation.
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DOI：
10.4049/jimmunol.1000646
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发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Boulares AH
中科院分区：
文献类型：
--
作者：
Zerfaoui M;Errami Y;Naura AS;Suzuki Y;Kim H;Ju J;Liu T;Hans CP;Kim JG;Abd Elmageed ZY;Koochekpour S;Catling A;Boulares AH
NF-κB在炎症基因表达中的作用及其参与慢性疾病和急性组织损伤的整个炎症过程的作用已被证实。我们和其他人已经证明了在炎症过程中聚（adp -核糖）聚合酶(PARP)-1的关键参与，部分是通过其与NF-κB的关系。然而，PARP-1影响NF-κB活化的机制尚不清楚。在这里，我们发现通过基因敲除、敲低或药物阻断PARP-1抑制TLR4刺激下平滑肌细胞（SMCs）中p65-NF-κB核易位、NF-κB dna结合活性以及随后的iNOS和ICAM-1表达。这些缺陷通过重组PARP-1表达得以逆转。PARP-1在lps诱导的I-κBα磷酸化和随后的降解中是不需要的，但在p65-NF-κB磷酸化中是必需的。在lps处理的PARP-1−/−细胞中，核周p65-NF-κB定位与输出而非输入缺陷有关。事实上，PARP-1缺乏并未改变输入蛋白α3和α4的表达及其胞质定位，但输出蛋白(Crm)-1的胞质水平升高。Crm1抑制促进p65-NF-κB核积累，逆转lps诱导的p65-NF-κB磷酸化、iNOS和ICAM-1表达。有趣的是，p65-NF-κB聚（adp -核糖基）化降低了其与体外Crm1的相互作用。在lps处理的SMCs中，PARP-1的药理抑制增加了p65-NF-κB-Crm1的相互作用。这些结果表明，p65-NF-κB聚（adp -核糖基）化可能是TLR4刺激下与Crm1相互作用及其核保留的关键决定因素。这些结果为PARP-1促进NF-κB核保留的机制提供了新的见解，并最终影响NF-κB依赖性基因的调控。
The role of NF-κB in the expression of inflammatory genes and its participation in the overall inflammatory process of chronic diseases and acute tissue injury are well-established. We and others have demonstrated a critical involvement of poly(ADP-ribose) polymerase (PARP)-1 during inflammation, in part, through its relationship with NF-κB. However, the mechanism by which PARP-1 affects NF-κB activation has been elusive. Here, we show that PARP-1 inhibition by gene knockout, knockdown, or pharmacological blockade prevented p65-NF-κB nuclear translocation in smooth muscle cells (SMCs) upon TLR4 stimulation, NF-κB DNA-binding activity, and subsequent iNOS and ICAM-1 expression. Such defects were reversed by reconstitution of PARP-1 expression. PARP-1 was dispensable for LPS-induced I-κBα phosphorylation and subsequent degradation but was required for p65-NF-κB phosphorylation. A perinuclear p65-NF-κB localization in LPS-treated PARP-1−/− cells was associated with an export rather an import defect. Indeed, while PARP-1 deficiency did not alter expression of importin α3 and α4 and their cytosolic localization, the cytosolic levels of exportin (Crm)-1 were increased. Crm1 inhibition promoted p65-NF-κB nuclear accumulation as well as reversed LPS-induced p65-NF-κB phosphorylation and iNOS and ICAM-1 expression. Interestingly, p65-NF-κB poly(ADP-ribosyl)ation decreased its interaction with Crm1 in vitro. Pharmacological inhibition of PARP-1 increased p65-NF-κB-Crm1 interaction in LPS-treated SMCs. These results suggest that p65-NF-κB poly(ADP-ribosyl)ation may be a critical determinant for the interaction with Crm1 and its nuclear retention upon TLR4 stimulation. These results provide novel insights into the mechanism by which PARP-1 promotes NF-κB nuclear retention, which ultimately can influence NF-κB-dependent gene regulation.
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影响因子：
3.7
作者：
Hans CP;Feng Y;Naura AS;Zerfaoui M;Rezk BM;Xia H;Kaye AD;Matrougui K;Lazartigues E;Boulares AH
通讯作者：
Boulares AH
影响因子：
3.8
作者：
Boulares, HA;Giardina, C;Cohen, SD
通讯作者：
Cohen, SD
影响因子：
4.8
作者：
Fagerlund, Riku;Melen, Krister;Julkunen, Ilkka
通讯作者：
Julkunen, Ilkka
DOI：
10.1165/rcmb.2001-0015oc
发表时间：
2003-03-01
影响因子：
6.4
作者：
Boulares, AH;Zoltoski, AJ;Smulson, ME
通讯作者：
Smulson, ME
影响因子：
4.8
作者：
Boulares, AH;Yakovlev, AG;Smulson, M
通讯作者：
Smulson, M