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Carbon dioxide regulates cholesterol levels through SREBP2 [1]

['Nityanand Bolshette', 'Department Of Biomolecular Sciences', 'Weizmann Institute Of Science', 'Rehovot', 'Saar Ezagouri', 'Vaishnavi Dandavate', 'Iuliia Karavaeva', 'Marina Golik', 'Hu Wang', 'The Sam']

Date: 2023-11

In mammals, O 2 and CO 2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O 2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO 2 signaling and adaptation. Here, we show that CO 2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO 2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO 2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO 2 signaling and that cellular cholesterol levels can be modulated by CO 2 through SREBP2.

Funding: G.A. is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences, Adelis Foundation, Susan and Michael Stern, Yotam project and the Weizmann institute sustainability and energy research initiative. I.K. received the Novo Nordisk Foundation postdoctoral fellowship. P.J.E. and T.F.O. are supported by grants from the National Institute of Health (HL077588 and GM149312 to P.J.E. and DK124343 to T.F.O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Bolshette et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

To identify signaling pathways that regulate gene expression in response to changes in CO 2 levels, and hence participate in CO 2 sensing, we employed a cell culture setup alongside high-throughput transcriptomic and biochemical analyses. We found that CO 2 activates a distinct transcriptional response that is dependent on SREBP2, a key regulator of cholesterol biosynthesis, to regulate the expression of cholesterogenic genes and cholesterol accumulation. SREBP2 regulation by CO 2 is likely mediated by changes in endoplasmic reticulum (ER) membrane cholesterol levels. We, thus, propose that SREBP2 plays a role in cellular CO 2 signaling and that SREBP2 regulation of cholesterol levels can be modulated by changes in CO 2 levels.

Carbon dioxide molecules are transported in the blood from body tissues to the lungs by one of 3 methods: dissolution directly into the blood, binding to hemoglobin, or carried as a bicarbonate ion. About 10% of CO 2 is dissolved in the plasma, a small fraction is bound to hemoglobin, while the majority (about 85%) is carried as a part of the bicarbonate buffer system [ 4 ]. In aqueous solution, CO 2 reacts with the water to form carbonic acid (H 2 CO 3 ), which is readily buffered by the bicarbonate buffer system to maintain the pH levels within the physiological range [ 8 ].

A fundamental process in mammalian physiology is oxygen (O 2 ) uptake from the environment into cells in exchange of carbon dioxide (CO 2 ), a byproduct of energy generation upon aerobic respiration. Oxygen is an essential substrate for cellular metabolism and bioenergetics and is indispensable for normal physiology and survival. Consequently, mammals have developed mechanisms to sense O 2 levels and regulate O 2 consumption in order to cope with conditions of insufficient O 2 supply. A principal regulator in the response to low oxygen levels is the hypoxia-inducible factor (HIF), which participates in sensing of low oxygen levels and subsequently activates a transcriptional program that facilitates cellular adaptation to changes in oxygen levels [ 1 – 3 ]. While the cellular response to oxygen levels is well characterized, relatively little is known regarding the mechanisms that participate in response to changes in CO 2 levels. It is noteworthy that CO 2 plays various critical roles in mammalian physiology including regulation of blood pH, respiratory drive, and O 2 affinity for hemoglobin [ 4 ]. Under physiological conditions, arterial blood CO 2 levels are tightly maintained approximately 35 to 45 mm Hg (approximately 5%). Altered CO 2 levels are associated with the pathophysiology of various diseases such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) as well as impaired wound healing and fibrosis [ 5 – 7 ].

Results

The transcriptional response to low CO 2 differs from pH To identify signaling pathways that participate specifically in CO 2 sensing and not changes in pH, we examined the global transcriptional response of cultured cells to reduction in CO 2 levels from 5% to 1%. We used special chambers with CO 2 , O 2 and temperature controls [9]. Temperature, O 2 and CO 2 , levels were continuously monitored throughout the experiment with constant temperature of 37°C and 20% O 2 . While CO 2 levels were modulated by replacing them with the inert nitrogen gas and were kept either at 5% or 1% (Fig 1A). PPT PowerPoint slide

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TIFF original image Download: Fig 1. The transcriptional response to low CO 2 levels compared to NaOH treatment. (A) A schematic depiction of the experimental design. NIH3T3 cells were cultured in media B (as detailed in method) at 37°C with 5% CO 2 and 20% oxygen. On day 4, cells were either untreated or treated with 18 mM NaOH or shifted to a special incubator (Coy Labs, USA) with 1% CO 2 and 20% oxygen. Cells and media were collected 2 and 4 h post treatment. RNA was extracted and analyzed by RNA sequencing (n = 4 for each time point per condition). (B) pH measurements of the growth media (mean ± SE, n = 3 biological replicates for each time point per condition, ***P < 0.001, nonsignificant (ns), two-sided Student’s t test). (C) PCA. (D) Heatmap representation of genes that were significantly altered (see Methods) between time points within conditions. Data are presented as row z-scores of the expression per condition. See also S1 Fig and S1 Table. The data underlying the graphs shown in the figure is included in S1 Data. Graphical illustrations were generated with BioRender.com. PCA, principal component analysis. https://doi.org/10.1371/journal.pbio.3002367.g001 As aforementioned, once CO 2 reacts with aqueous solution it forms carbonic acid and acidifies it. Since the reduction in CO 2 levels from 5% to 1% resulted in alkaline condition, we also used 18 mM NaOH to alkalize the media as a control for changes that are purely pH-dependent. Importantly, under both conditions, namely 1% CO 2 or 18 mM NaOH, the media pH at 2 and 4 h post exposure was similar (approximately 7.7) and differed from that of control cells (5% CO 2 ), which maintained pH across the normal physiological range (approximately 7.3) (Fig 1B). NIH3T3 cells (a fibroblast cell line that was isolated from mouse NIH/Swiss embryos) were harvested 2 and 4 h post exposure, RNA was extracted and analyzed by RNA-sequencing. The transcriptomic analysis revealed that the transcriptional response differed between the low CO 2 exposure and the alkaline conditions, even though the pH was similar (Figs 1C and 1D and S1). Notably, principal component analysis (PCA) and unsupervised clustering analyses (Fig 1C and 1D) clearly discriminated between exposure to low CO 2 versus NaOH treatment. NaOH treatment induced a prominent effect on gene expression with 2,697 genes showing differential response (P adj. < = 0.05, |log2FC| > = 1, baseMean > = 5), with 1,320 up- and 1,377 down-regulated. While exposure to a low CO 2 level led to a milder effect on gene expression (1,328 genes with 685 up- and 643 down-regulated) (S1A and S1B Fig). Although, both the up- and down-regulated genes overlapped between the CO 2 and NaOH groups, we found in line with the PCA and cluster analyses that a significant number of genes are uniquely altered in response to CO 2 (S1B Fig). Overall, our analyses show that under similar alkaline pH, the transcriptional response differs between low CO 2 and NaOH treatments. Thus, supporting a distinct mechanism that is activated in response to changes in CO 2 levels to regulate gene expression.

CO 2 alters the expression of genes that participate in cholesterol biosynthesis To identify potential transcription factors that participate in gene expression regulation in response to CO 2 or NaOH, we took an advantage of our time course analysis and performed unbiased cluster analysis (Fig 2A). We identified 3 major clusters; Cluster 1: Transcripts that were monotonically down-regulated (CO 2 or NaOH; 511 and 1,102, respectively); Cluster 2: Transcripts that were up-regulated exclusively after 2 h (CO 2 or NaOH; 206 and 463, respectively); and Cluster 3: Transcripts that were monotonically up-regulated (CO 2 or NaOH; 315, and 606, respectively). Next, to uncover related biological processes affected by each treatment, we performed pathway enrichment analysis on each cluster. Remarkably, we found that cholesterol biosynthesis and its related processes are highly enriched in response to CO 2 but not to NaOH, specifically in cluster 3 which includes the monotonically up-regulated transcripts (Fig 2B). These findings indicated that low CO 2 induces the expression of genes implicated in cholesterol metabolism and that this effect is not a mere response to alkaline conditions, as it was not apparent upon NaOH treatment. This prompted us to specifically examine expression pattern of enzymes involved in de novo cholesterol biosynthesis based on our RNA-sequencing data. The vast majority of enzymes involved in different stages of cholesterol biosynthesis were up-regulated in cells exposed to low CO 2 . Notably, the induction of these transcripts was mostly absent in NaOH-treated cells (Fig 2C and 2D). Furthermore, analysis of cholesterogenic gene expression by qPCR showed that in most cases their transcript levels are specifically induced by low CO 2 levels but not upon NaOH treatment (Fig 2E). These results were in line with the above detailed RNA-sequencing analysis. A similar trend was observed in hepatocyte murine cell line (Hepa1c1) (S2A Fig). In addition, these effects were recapitulated in primary tail fibroblasts and primary muscles, but not in primary white or brown adipocytes (S2A Fig). PPT PowerPoint slide

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TIFF original image Download: Fig 2. Low CO 2 levels specifically induce the expression of genes related to cholesterol biosynthesis. (A) K-means unsupervised clustering of significant genes for each of the conditions. Black line represents the mean z-score (for gene lists see S2 Table). (B) Pathway enrichment analysis was performed using the IPA tool for the genes included in each of the clusters for 1% CO 2 or 18 mM NaOH treatments. Presented are the top 3 enriched pathways in each cluster based on P value (for full list of pathways, see S3 Table). (C) Schematic illustration of the cholesterol biosynthesis pathway alongside genes that were significantly affected by the treatments. Color indicates on the condition in which the genes are affected. (D) Heatmap representation of cholesterogenic genes that were significantly affected by any of the conditions presented. Data are presented as row z-score of the average expression per condition (n = 4 biological replicates). (E) Quantitative PCR analysis of cholesterogenic gene expression levels from NIH3T3 cells treated with 1% CO 2 or 18 mM NaOH (mean ± SE, n = 5 biological replicates per time point per condition, *P < 0.05, **P < 0.01, ***P < 0.001, nonsignificant (ns), two-way ANOVA with Tukey’s post hoc test) (see also S2 and S3 Figs and S2 and S3 Tables). The data underlying the graphs shown in the figure is included in S1 Data. IPA, ingenuity pathway analysis. https://doi.org/10.1371/journal.pbio.3002367.g002 Next, we examined the effect of hypercapnia, namely elevated CO 2 level, on cholesterogenic gene expression. Cells were exposed to increased CO 2 level (i.e., 10%) for 2 and 4 h and the transcript levels of cholesterogenic genes were analyzed by qPCR. Here again, O 2 level was maintained constant at 20% using our CO 2 , O 2 and temperature-controlled chambers. High CO 2 levels elicited the opposite effect to lower CO 2 levels and the expression levels of cholesterogenic genes were suppressed (S2B Fig). Comparison of gene expression data of THP-1 monocytes exposed to 10% CO 2 [10] with our NIH3T3 cells data (1% CO 2 exposure) showed a small overlap in the responsive genes (S3A Fig). Yet, this small group included cholesterogenic genes (e.g., Ldlr, Idi1, Insig1, Hmgcs1, Dhcr7) and their response was in line with our findings, namely 10% CO 2 repressed of their expression (e.g., Insig1, Hmgcs1) (S3B Fig). Taken together, our analyses reveal that alteration of CO 2 levels from the physiological range modulate the expression of genes involved in cholesterol homeostasis. Reduced and elevated CO 2 levels activate and repress their expression, respectively.

SREBP2 is activated in response to low CO 2 to induce the expression of cholesterogenic genes SREBP2 is a key transcriptional regulator of genes involved in cholesterol biosynthesis [11,12]. In response to changes in cholesterol levels, SREBP2 translocates from the ER to the Golgi, where subsequent cleavage occurs and the N-terminal form of SREBP2 shuttles to the nucleus and activates the expression of transcripts involved in cholesterol biosynthesis [13]. Our transcription factor analysis predicted SREBP2 among the top potential transcriptional regulators for the expression of genes that are up-regulated (clusters 2 and 3) upon exposure to low CO 2 but not in response to NaOH treatment (Fig 3A and 3B). PPT PowerPoint slide

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TIFF original image Download: Fig 3. Low CO 2 levels activate SREBP2 and induce the expression of cholesterogenic genes through SRE. (A, B) Upstream regulator analysis was performed with IPA for clusters 2 and 3 within each condition. The top transcription factors, with the highest p-value, are presented (for full list, see S4 Table). (C) Immunoblot of total cell extracts from NIH3T3 cells exposed to either 5% CO 2 or 1% CO 2 p—SREBP2 precursor (approximately 126 kD); c—SREBP2 cleaved form (approximately 68 kD) (pooled sample of n = 3 biological replicates). (D) Immunoblot of cytoplasmic (Cyto-extract) and nuclear fractions (Nu-extract) from NIH3T3 cells exposed to either 5% or 1% CO 2 for 4 h (pooled sample of n = 3 biological replicates). (E) Total cholesterol quantification of NIH3T3 cells that were exposed to 5% or 1% CO 2 for 0, 3, 6, 12, 24 h (mean ± SE, n = 3 biological replicates per condition, ***P < 0.001, nonsignificant (ns), two-way ANOVA with Bonferroni’s multiple comparisons test). (F) Quantitative PCR analysis for expression levels of cholesterol biosynthesis-related genes from control (siNTC) or SREBP2 silenced (siSREBP2) NIH3T3 cells exposed to 5% or 1% CO 2 for 4 h (mean ± SE, n = 3 biological replicates per condition, ***P < 0.001, **P < 0.01, nonsignificant (ns), two-way ANOVA with Bonferroni’s multiple comparisons test). (G) Immunoblot of NIH3T3 cells under the same condition as in (F) (pooled sample of n = 3 biological replicates). (H) Bioluminescence recordings from NIH3T3 cells transfected with SRE-Luc reporter plasmid (WT-SRE) and exposed to DMSO (control), 20 μm simvastatin or 20 μm simvastatin + 20 μm fatostatin, black arrow indicates the time of treatment (mean ± SE, n = 3 biological replicates per condition, AUC for control 1.14 ± 0.009, simvastatin 4.05 ± 0.06 (P < 0.0001), simvastatin + fatostatin 1.33 ± 0.04 (P < 0.0001), two-sided Student’s t test). (I) Bioluminescence recordings from NIH3T3 cells transfected with WT SRE-Luc, mutant SRE-Luc, or control vector (CMV-Luc), and exposed to either 5% or 1% CO 2 , the red arrow indicates the shift in CO 2 levels (mean ± SE, n = 6 biological replicates per condition, AUC for SRE Luc 5% CO 2 1.24 ± 0.03, 1% CO 2 2.77 ± 0.01 (P < 0.0001), mSRE Luc 5% CO 2 0.83 ± 0.02, 1% CO 2 0.91 ± 0.01 (P < 0.002), CMV Luc 5% CO 2 0.33 ± 0.007, 1% CO2 0.42 ± 0.01 (P < 0.001), two-sided Student’s t test) (see also S4 and S5 Figs). The data underlying the graphs shown in the figure is included in S1 Data. AUC, area under curve; IPA, ingenuity pathway analysis; SRE, sterol regulatory element. https://doi.org/10.1371/journal.pbio.3002367.g003 We, therefore, hypothesized that SREBP2 is activated in response to low CO 2 to induce the expression of enzymes involved in cholesterol biosynthesis. To test this, cultured cells were exposed to low CO 2 and SREBP2 was analyzed by SDS-PAGE and immunoblot analysis. We found that the cleaved form of SREBP2 (approximately 68 kD) accumulates 2 and 4 h following exposure to low CO 2 levels (Fig 3C). This effect was specific to low CO 2 and not to alkalic pH as it was not observed in NaOH-treated cells (S4A Fig). Biochemical nuclear-cytoplasmic fractionation further showed that the cleaved form of SREBP2 accumulates in the nucleus upon exposure to low CO 2 levels (Fig 3D). Together, our findings indicate that the SREBP2 signaling pathway is activated upon exposure to low CO 2 levels. To examine the functional consequence of SREBP2 and its downstream gene activation, we performed a time course analysis (0, 3, 6, 12, and 24 h) and measured cholesterol levels in cells cultured either at 5% or 1% CO 2 . Upon 24 h exposure to low CO 2 levels, cells accumulated cholesterol, in line with SREBP2 activation and elevated the expression of cholesterogenic genes (Fig 3E). Next, we asked whether the induction of cholesterogenic genes under low CO 2 is SREBP2-dependent. To this end, cells were transfected with either control siRNA (siNTC-Non Template Control) or siRNA against mouse SREBP2 (siSREBP2) and were exposed either to 1% CO 2 or 5% CO 2 for 4 h. As expected, SREBP2 was undetectable in siSREBP2-silenced cells under both 5% and 1% CO 2 and the basal expression levels of SREBP2 target genes was lower (Fig 3F and 3G). Control cells showed accumulation of the cleaved form of SREBP2 upon 1% CO 2 as well as induction of its cholesterogenic target genes (Fig 3F and 3G). Importantly, the induction of cholesterogenic genes was completely abolished in SREBP2 silenced cells under low CO 2 levels, indicating that the effect is SREBP2-dependent (Fig 3F). We also identified several transcripts that are induced upon low CO 2 levels in our gene expression analysis yet their induction was SREBP2-independent (S4B Fig). It is conceivable that the response to low CO 2 levels is coordinated through the concerted action of several transcription regulators and is not exclusively SREBP2-dependent. Overall, our results suggest that low CO 2 levels elicit SREBP2 cleavage and nuclear accumulation to induce the expression of its target genes, primarily cholesterogenic genes and consequently cholesterol accumulation.

Low CO 2 activates gene expression through a sterol regulatory element SREBP2 activates the transcription of its downstream targets by binding to a specific region on the promoter sequence known as sterol regulatory element (SRE) [14]. To examine whether low CO 2 levels can activate gene expression through an SRE, we employed an SRE reporter assay. This reporter is based on the HMG-CoA synthase promoter sequence harboring SRE that drive the expression of a firefly luciferase [15]. Cells were transfected with the SRE reporter and bioluminescence was continuously monitored. Consistent with the activation of SRE by SREBP2, treatment with simvastatin, which inhibits de novo cholesterol biosynthesis [16] and activates SREBP2, resulted in increased bioluminescence. This effect was suppressed upon co-administration of fatostatin (Fig 3H), which inhibits SREBP2 ER-to-Golgi translocation [17]. Then, we tested the effect of low CO 2 on the reporter activity. In line with above-described findings, a decrease in CO 2 levels from 5% to 1% induced an increase in bioluminescence of cells expressing the wild-type reporter (pSynSRE-T-Luc) (Fig 3I). A decrease in CO 2 levels had no effect on the bioluminescence of cells expressing either a mutant reporter (pSynSRE-Mut-T-Luc) [18] or a control luciferase reporter (pcDNA3-Luc) (Fig 3I). Consistently, an increase in CO 2 levels from 5% to 10% markedly suppressed the bioluminescence from cells expressing a wild type but not a control luciferase reporter (S5A Fig). In our bioluminescence reporter assays, we observed an initial minor response that was not SRE-specific and was evident in the control reporters as well. This unspecific response likely stems from the effect of pH changes on bioluminescence in general [19]. Next, we employed our reporter assay to examine whether SRE activation by low CO 2 is reversible. To this end, cells expressing wild-type SRE reporter were exposed to either constant 5% as a control or interchanging 5% to 1% CO 2 levels and bioluminescence was continuously recorded. A shift in CO 2 levels from 5% to 1% increased the bioluminescence levels. This increase was reduced back to basal levels once CO 2 levels were shifted to 5% (S5B Fig). This result indicates that CO 2 reversibly modulate SRE activation and likely SREBP2 activation. Taken together, our results suggest that an intact SRE is sufficient for the transcriptional response to changes in CO 2 levels and the effects of CO 2 levels on it are reversible.

Stability of the mature cleaved form of SREBP2 is not affected by low CO 2 levels SREBP2 translocates from the ER-to-Golgi and subsequently reaches the nucleus to induce gene expression. The exit of SREBP2 from the ER is regulated by sterol levels via SREBP cleavage-activating protein (SCAP) and insulin-induced gene (INSIG). Low ER cholesterol levels destabilize INSIG-SCAP interaction and successively enable the SREBP2-SCAP complex to translocate from the ER to Golgi where SREBP2 is cleaved [20]. The mature N-terminal cleaved form of SREBP2 then shuttles to the nucleus [13] to activate gene expression as aforementioned through SRE sites on target genes [21]. Hitherto, we showed that upon low CO 2 levels SREBP2 is cleaved, the N-terminal cleaved form accumulates in the nucleus and can activate gene expression though an intact SRE site (Fig 3). To identify the signaling node though which SREBP2 is activated in response to low CO 2 levels, we systematically examined the different steps in the SREBP2 signaling pathway (S6A Fig) comparing sterol depletion with exposure to low CO 2 levels. In the nucleus, the levels of mature cleaved form of SREBP2 are regulated by its proteasomal degradation [22] as stabilization of the nuclear form by proteasome inhibition or defective polyubiquitination actively induce its target genes [23,24]. We hypothesized that low CO 2 levels might alter nuclear SREBP2 turnover and thereby induce its nuclear accumulation and target gene expression. To test this, we exogenously expressed in cultured NIH3T3 cells a FLAG-tagged truncated mature SREBP2 fragment (FLAG N-SREBP2) [25], which was shown to localize in the nucleus [26]. Cells were exposed either to sterol depletion upon methyl-β-cyclodextrin (MBCD) treatment or to 1% CO 2 levels. Total protein extracts were prepared and analyzed by immunoblot with either anti-SREBP2 or anti-FLAG antibody to detect the endogenous or the exogenously expressed truncated forms, respectively. Both MBCD treatment and exposure to low CO 2 induced the accumulation of the endogenous cleaved form of SREBP2 (S6B Fig). However, neither treatment affected the levels of the exogenously expressed cleaved form (i.e., FLAG N-SREBP2) (S6C Fig), suggesting that low CO 2 levels, similar to sterol depletion by MBCD do not affect the nuclear stability of the cleaved mature form of SREBP2.

Low CO 2 levels induce the ER-to-Golgi translocation of SREBP2 SCAP-SREBP2 ER-to-Golgi translocation is a critical step in SREBP2 activation and subsequent induction of its target genes. To examine whether the activation of SREBP2 upon low CO 2 is dependent on its ER-to-Golgi trafficking, we employed fatostatin, which pharmacologically blocks the ER-to-Golgi transport of SCAP-SREBP2 [17]. Cells were exposed to either fatostatin or DMSO as control under 5% or 1% CO 2 . Low CO 2 levels induced the accumulation of the mature cleaved form of SREBP2. Importantly, this effect was blocked in the presence of fatostatin (S6D Fig). Consistently, the induction of SREBP2 target genes in response to low CO 2 levels was eliminated in the presence of fatostatin (S6E Fig). This result indicated that ER-to-Golgi trafficking is necessary for activation of SREBP2 by low CO 2 levels. As aforementioned, SCAP regulates SREBP2 transport in a sterol-dependent fashion as it retains the SCAP-INSIG-SREBP2 complex in the ER membrane and inhibits the subsequent processing of SREBP2, namely, its cleavage and ER-Golgi translocation [27]. We, therefore, examined whether activation of SREBP2 by low CO 2 levels is also SCAP-sensitive. We employed siRNA to knockdown SCAP and exposed control (siNTC) or SCAP knockdown (siSCAP) cells to low CO 2 levels (i.e., 1%). Low SCAP levels in cultured cells were shown to suppress SREBP2 proteolysis and expression of SREBP2 downstream target genes [28,29]. The induction of SREBP2 target genes in response to low CO 2 levels was as well suppressed in SCAP-deficient cells likely due to inhibition of SREBP2-SCAP ER-to-Golgi translocation (S6F Fig). Together, our analyses suggest that activation and induction of SREBP2 target genes upon low CO 2 levels is dependent on ER-to-Golgi trafficking and regulated by SCAP. Hence, it seems to follow the canonical pathway of SREBP2 activation as in response to low sterol levels.

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