Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling.
Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling.
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DOI：
10.3389/fcimb.2012.00080
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发表时间：
2012
影响因子：
5.7
通讯作者：
Wilson BA
中科院分区：
文献类型：
--
作者：
Bannai Y;Aminova LR;Faulkner MJ;Ho M;Wilson BA
来自多杀性巴氏杆菌（PMT）、博德特氏菌（DNT）、大肠杆菌（CNF 1 -3）和耶尔森氏菌（CNFY）的皮肤坏死毒素通过活性位点Gln残基的脱酰胺和/或转谷氨酰胺作用调节其G蛋白靶标，这导致G蛋白及其同源下游信号传导途径的活化。DNT和CNF作用于小的Rho GTPases，而PMT作用于异源三聚体Gq、GI和G12/13蛋白的α亚基。我们以前证明PMT通过下调Notch 1和稳定β-catenin和Pref 1/Dlk 1（与细胞命运决定（包括脂肪和骨骼发育）密切相关的信号通路中的关键蛋白），以非钙调神经磷酸酶依赖的方式有效阻断脂肪形成和脂肪细胞分化。在这里，我们报道了与PMT类似，DNT和CNF 1通过阻止脂肪细胞标志物PPARγ和C/EBPα的上调，同时稳定Pref 1/Dlk 1和β-catenin的表达，完全阻断脂肪形成和脂肪细胞分化。我们发现Rho/ROCK抑制剂Y-27632阻止或逆转了这些毒素介导的作用，强烈支持Rho/ROCK信号在皮肤坏死毒素介导的脂肪生成和脂肪细胞分化抑制中的作用。毒素处理还伴随着Notch 1表达的下调，尽管这种抑制独立于Rho/ROCK信号传导。我们进一步表明，PMT介导的Notch 1表达下调主要通过G12/13信号传导发生。我们的研究结果揭示了皮肤坏死毒素对脂肪细胞分化的作用途径的新细节，以及Rho/ROCK信号在介导毒素对Wnt/β-catenin和Notch 1信号的作用中的作用，特别是Gq和G12/13在介导PMT对Rho/ROCK和Notch 1信号的作用中的作用。
The dermonecrotic toxins from Pasteurella multocida (PMT), Bordetella (DNT), Escherichia coli (CNF1-3), and Yersinia (CNFY) modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downstream signaling pathways. Whereas DNT and the CNFs act on small Rho GTPases, PMT acts on the α subunit of heterotrimeric Gq, Gi, and G12/13 proteins. We previously demonstrated that PMT potently blocks adipogenesis and adipocyte differentiation in a calcineurin-independent manner through downregulation of Notch1 and stabilization of β-catenin and Pref1/Dlk1, key proteins in signaling pathways strongly linked to cell fate decisions, including fat and bone development. Here, we report that similar to PMT, DNT, and CNF1 completely block adipogenesis and adipocyte differentiation by preventing upregulation of adipocyte markers, PPARγ and C/EBPα, while stabilizing the expression of Pref1/Dlk1 and β-catenin. We show that the Rho/ROCK inhibitor Y-27632 prevented or reversed these toxin-mediated effects, strongly supporting a role for Rho/ROCK signaling in dermonecrotic toxin-mediated inhibition of adipogenesis and adipocyte differentiation. Toxin treatment was also accompanied by downregulation of Notch1 expression, although this inhibition was independent of Rho/ROCK signaling. We further show that PMT-mediated downregulation of Notch1 expression occurs primarily through G12/13 signaling. Our results reveal new details of the pathways involved in dermonecrotic toxin action on adipocyte differentiation, and the role of Rho/ROCK signaling in mediating toxin effects on Wnt/β-catenin and Notch1 signaling, and in particular the role of Gq and G12/13 in mediating PMT effects on Rho/ROCK and Notch1 signaling.
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影响因子：
2.9
作者：
Amano, Mutsuki;Nakayama, Masanori;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
影响因子：
3.1
作者：
Brockmeier, SL;Register, KB;Kunkle, RA
通讯作者：
Kunkle, RA
影响因子：
6.2
作者：
Harmey, D;Stenbeck, G;Grigoriadis, AE
通讯作者：
Grigoriadis, AE
影响因子：
4.8
作者：
Garces, C;RuizHidalgo, MJ;Laborda, J
通讯作者：
Laborda, J
影响因子：
3.1
作者：
Hildebrand, Dagmar;Heeg, Klaus;Kubatzky, Katharina F.
通讯作者：
Kubatzky, Katharina F.