scholarly journals N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H

2010 ◽  
Vol 123 (9) ◽  
pp. 1438-1448 ◽  
Author(s):  
C.-P. Chan ◽  
T.-Y. Mak ◽  
K.-T. Chin ◽  
I. O.-L. Ng ◽  
D.-Y. Jin
2020 ◽  
Author(s):  
Yoshimi Nakagawa ◽  
Yunong Wang ◽  
Song-iee Han ◽  
Kanako Okuda ◽  
Asayo Oishi ◽  
...  

SummaryCREB3L3 is a membrane-bound transcription factor to maintain lipid metabolism in the liver and small intestine. CREB3L3 ablation in Ldlr-/- mice exacerbated hyperlipidemia with remnant ApoB-containing lipoprotein accumulation, developing enhanced aortic atheroma formation, whose extent was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly upregulates anti-atherogenic FGF21 and ApoA4, whereas antagonizes hepatic SREBP-mediated lipogenic and cholesterogenic genes and regulates LXR-regulated genes involved in intestinal transport of cholesterol. CREB3L3 deficiency accumulates nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs on endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 competitively antagonizes SREBPs for ER-Golgi transport, resulting in ER retention and proteolytic activation inhibition at Golgi, and vice versa. Collectively, due to this new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions, CREB3L3 has multi-potent protective effects against atherosclerosis.


Open Biology ◽  
2012 ◽  
Vol 2 (7) ◽  
pp. 120091 ◽  
Author(s):  
Matthew D. Rolfe ◽  
Andrea Ocone ◽  
Melanie R. Stapleton ◽  
Simon Hall ◽  
Eleanor W. Trotter ◽  
...  

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless, statistical approaches to infer TF activities have yielded non-trivial and verifiable predictions for individual TFs. Here, global statistical modelling identifies changes in TF activities from transcript profiles of Escherichia coli growing in stable (fixed oxygen availabilities) and dynamic (changing oxygen availability) environments. A core oxygen-responsive TF network, supplemented by additional TFs acting under specific conditions, was identified. The activities of the cytoplasmic oxygen-responsive TF, FNR, and the membrane-bound terminal oxidases implied that, even on the scale of the bacterial cell, spatial effects significantly influence oxygen-sensing. Several transcripts exhibited asymmetrical patterns of abundance in aerobic to anaerobic and anaerobic to aerobic transitions. One of these transcripts, ndh , encodes a major component of the aerobic respiratory chain and is regulated by oxygen-responsive TFs ArcA and FNR. Kinetic modelling indicated that ArcA and FNR behaviour could not explain the ndh transcript profile, leading to the identification of another TF, PdhR, as the source of the asymmetry. Thus, this approach illustrates how systematic examination of regulatory responses in stable and dynamic environments yields new mechanistic insights into adaptive processes.


2001 ◽  
Vol 61 (7) ◽  
pp. 915-920 ◽  
Author(s):  
Zi-Jiang Chen ◽  
Dong-Li Song ◽  
Zhenhua Miao ◽  
Chung-Ho Chang

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ciara M Gallagher ◽  
Carolina Garri ◽  
Erica L Cain ◽  
Kenny Kean-Hooi Ang ◽  
Christopher G Wilson ◽  
...  

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.


1983 ◽  
Vol 213 (1) ◽  
pp. 99-105 ◽  
Author(s):  
S R Wilson ◽  
M D Houslay

Dithiothreitol led to the activation and solubilization of the cyclic nucleotide phosphodiesterase activities associated with the smooth and various rough subfractions of rat liver endoplasmic reticulum. The activity in each of the subfractions exhibited somewhat different time courses, and sensitivities to dithiothreitol concentration, in respect of their solubilization and activation. Both activation and solubilization by dithiothreitol could be blocked by either thiol proteinase inhibitors or excess bovine serum albumin. Freeze-thaw solubilization was not blocked by the thiol proteinase inhibitor antipain and did not lead to the activation of the enzyme. After dithiothreitol-induced solubilization, all of the enzymes exhibited non-linear Lineweaver-Burk plots indicative of apparent negative co-operativity. In contrast, after freeze-thaw solubilization the enzyme in the smooth-endoplasmic-reticulum-plus-Golgi fraction still obeys Michaelis kinetics, as does the membrane-bound enzyme. It is possible to mimic the action of dithiothreitol in solubilizing and activating the enzyme by limited proteolysis with trypsin. Triton X-100 is highly efficient at solubilizing these enzymes, yet has little effect on their activities. Charged detergents exhibit highly selective effects on the enzymes as regards their solubilization and activity expressed.


2010 ◽  
Vol 427 (3) ◽  
pp. 359-367 ◽  
Author(s):  
Pil Joon Seo ◽  
Mi Jung Kim ◽  
Jin-Su Song ◽  
Youn-Sung Kim ◽  
Hie-Joon Kim ◽  
...  

Changes in membrane fluidity are the earliest cellular events that occur in plant cells upon exposure to cold. This subsequently triggers physiological processes, such as calcium influx and reorganization of actin cytoskeletons, and induces expression of cold-responsive genes. The plasma-membrane-anchored NAC (NAM/ATAF/CUC) transcription factor NTL6 is of particular interest. Cold triggers proteolytic activation of the dormant NTL6 protein, which in turn elicits pathogen-resistance responses by inducing a small group of cold-inducible PR (pathogenesis-related) genes in Arabidopsis. In the present study, we show that proteolytic processing of NTL6 is regulated by cold-induced remodelling of membrane fluidity. NTL6 processing was stimulated rapidly by cold. The protein stability of NTL6 was also enhanced by cold. The effects of cold on NTL6 processing and protein stability were significantly reduced in cold-acclimatized plants, supporting the regulation of NTL6 processing by membrane fluidity. Consistent with this, although NTL6 processing was stimulated by pharmacological agents that reduce membrane fluidity and thus mimic cold, it was inhibited when plants were treated with a 18:3 unsaturated fatty acid, linolenic acid. In addition, the pattern of NTL6 processing was changed in Arabidopsis mutants with altered membrane lipid compositions. Assays employing chemicals that inhibit activities of the proteasome and proteases showed that NTL6 processing occurs via the regulated intramembrane proteolysis mechanism. Interestingly, a metalloprotease inhibitor blocked the NTL6 processing. These observations indicate that a metalloprotease activity is responsible for NTL6 processing in response to cold-induced changes in membrane fluidity.


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