Christine R. Montague

Cornell University

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Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

eLife (2017)

Evgeniya V. Nazarova Christine R. Montague Thuy La Kaley M. Wilburn Neelima Sukumar

Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability. We also demonstrate that Mce1 functions as a fatty acid transporter in Mtb and determine that facilitating cholesterol and fatty acid import via Rv3723/LucA is required for full bacterial virulence in vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key function for Rv3723/LucA in in coordinating thetransport of both these substrates.

Assimilation (phonology)

10.7554/elife.26969

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Citations (160)

NAC and DTT promote TGF-β1 monomer formation: demonstration of competitive binding

Journal of Inflammation (2006)

Frank Lichtenberger Christine R. Montague Melissa Hunter Gwyn E. Frambach Clay B. Marsh

Abstract TGF-β plays an important role in the genesis and progression of pulmonary fibrosis. We sought to determine the role of mononuclear phagocytes in the activation of TGF-β and found that freshly isolated peripheral blood monocytes spontaneously released TGF-β. Stimulating these monocytes with GM-CSF or LPS, but not MCSF, augmented the activation of TGF-β. In human monocytes, the free thiol compounds DTT and NAC decreased the activity of TGF-β, without affecting TGF-β mRNA transcription. Both NAC and DTT lessened the biological activity of recombinant active TGF-β in a cell-free system. We found that NAC and DTT reduced dimeric active TGF-β from a 25 kDa protein to 12.5 kDa inactive monomer. This conversion was reversed using the oxidizing agent diamide. Diamide also restored biological activity to NAC or DTT-treated TGF-β. Reduction of TGF-β to monomers could competitively inhibit active dimeric TGF-β and block intracellular signaling events. Our observations suggest that modulation of the oxidative state of TGF-β may be a novel therapeutic approach for patients with pulmonary fibrosis.

10.1186/1476-9255-3-7

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Citations (15)

MceG stabilizes the Mce1 and Mce4 transporters in Mycobacterium tuberculosis

Journal of Biological Chemistry (2023)

Rachael A Fieweger Kaley M. Wilburn Christine R. Montague Emma K. Roszkowski Carolyn M. Kelly

10.1016/j.jbc.2023.102910

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Citations (4)

Science Translational Medicine (2011)

John Huynh Nozomi Nishimura Kuldeepsinh Rana John M. Peloquin Joseph P. Califano

Inhibiting endothelial cell contractility reverses the deleterious effects of age-related matrix stiffening on normal cell function, which could help prevent the development of atherosclerosis.

Stiffening

10.1126/scitranslmed.3002761

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Citations (370)

Regulation of α₂-adrenoceptors in human vascular smooth muscle cells

AJP Heart and Circulatory Physiology (2004)

Maqsood A. Chotani Srabani Mitra Baogen Y. Su Sheila Flavahan Ali H. Eid

This study analyzed the regulation of α 2 -adrenoceptors (α 2 -ARs) in human vascular smooth muscle cells (VSMs). Saphenous veins and dermal arterioles or VSMs cultured from them expressed high levels of α 2 -ARs (α 2C > α 2A , via RNase protection assay) and responded to α 2 -AR stimulation [5-bromo- N-(4,5-dihydro-1 H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304, 1 μM)] with constriction or calcium mobilization. In contrast, VSMs cultured from aorta did not express α 2 -ARs and neither cultured cells nor intact aorta responded to UK-14,304. Although α 2 -ARs (α 2C >> α 2A ) were detected in aortas, α 2C -ARs were localized by immunohistochemistry to VSMs of adventitial arterioles and not aortic media. In contrast with aortas, aortic arterioles constricted in response to α 2 -AR stimulation. Reporter constructs demonstrated higher activities for α 2A - and α 2C -AR gene promoters in arteriolar compared with aortic VSMs. In arteriolar VSMs, serum increased expression of α 2C -AR mRNA and protein but decreased expression of α 2A -ARs. Serum induction of α 2C -ARs was reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) with 2 μM SB-202190 or dominant-negative p38 MAPK. UK-14,304 (1 μM) caused calcium mobilization in control and serum-stimulated cells: in control VSMs, the response was inhibited by the α 2A -AR antagonist BRL-44408 (100 nM) but not by the α 2C -AR antagonist MK-912 (1 nM), whereas after serum stimulation, MK-912 (1 nM) but not BRL-44408 (100 nM) inhibited the response. These results demonstrate site-specific expression of α 2 -ARs in human VSMs that reflects differential activity of α 2 -AR gene promoters; namely, high expression and function in venous and arteriolar VSMs but no detectable expression or function in aortic VSMs. We found that α 2C -ARs can be dramatically and selectively induced via a p38 MAPK-dependent pathway. Therefore, altered expression of α 2C -ARs may contribute to pathological changes in vascular function.

10.1152/ajpheart.00268.2003

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Citations (101)

Activation of Estrogen Receptor-α Reduces Aortic Smooth Muscle Differentiation

Circulation Research (2006)

Christine R. Montague Melissa Hunter Mikhail A. Gavrilin Gary Phillips Pascal J. Goldschmidt‐Clermont

Women are at high risk of dying from unrecognized cardiovascular disease. Many differences in cardiovascular disease between men and women appear to be mediated by vascular smooth muscle cells (SMC). Because estrogen reduces the proliferation of SMC, we hypothesized that activation of estrogen receptor-alpha (ERalpha) by agonists or by growth factors altered SMC function. To determine the effect of growth factors, estrogen, and ERalpha expression on SMC differentiation, human aortic SMC were cultured in serum-free conditions for 10 days. SMC from men had lower spontaneous expression of ERalpha and higher levels of the differentiation markers calponin and smooth muscle alpha-actin than SMC from women. When SMC containing low expression of ERalpha were transduced with a lentivirus containing ERalpha, activation of the receptor by ligands or growth factors reduced differentiation markers. Conversely, inhibiting ERalpha expression by small interfering RNA (siRNA) in cells expressing high levels of ERalpha enhanced the expression of differentiation markers. ERalpha expression and activation reduced the phosphorylation of Smad2, a signaling molecule important in differentiation of SMC and initiated cell death through cleavage of caspase-3. We conclude that ERalpha activation switched SMC to a dedifferentiated phenotype and may contribute to plaque instability.

Estrogen receptor alpha

Calponin

Estrogen receptor beta

10.1161/01.res.0000238376.72592.a2

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Citations (34)

Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling

Molecular Microbiology (2017)

Richard Johnson Guangchun Bai Christopher M. DeMott Nilesh K. Banavali Christine R. Montague

Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium. Metabolic inhibition by V-58 was carbon source dependent in Mtb and did not occur in Mycobacterium smegmatis, suggesting that V-58-mediated growth inhibition is due to interference with specific Mtb metabolic pathways rather than a generalized cAMP toxicity. Chemical stimulation of cAMP production by Mtb within macrophages also caused down regulation of TNF-α production by the macrophages, indicating a complex role for cAMP in Mtb pathogenesis. Together these studies describe a novel approach for targeted stimulation of cAMP production in Mtb, and provide new insights into the myriad roles of cAMP signaling in Mtb, particularly during Mtb's interactions with macrophages.

Mycobacterium smegmatis

10.1111/mmi.13701

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Citations (36)

Estradiol increases platelet aggregation in PlA1/A1 individuals

American Heart Journal (2006)

Konstantinos Dean Boudoulas Christine R. Montague Pascal J. Goldschmidt‐Clermont Glen E. Cooke

10.1016/j.ahj.2005.07.036

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Citations (11)

Rv3723/LucA coordinates fatty acid and cholesterol uptake inMycobacterium tuberculosis

bioRxiv (Cold Spring Harbor Laboratory) (2017)

Evgeniya V. Nazarova Christine R. Montague Thuy La Kaley M. Wilburn Neelima Sukumar

Abstract Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts and Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infection in mammals. While the uptake of cholesterol by Mtb is mediated by the Mce4 transporter, the route(s) of uptake of fatty acids remain unknown. Here, we demonstrate that an uncharacterized protein LucA, integrates the assimilation of both cholesterol and fatty acids in Mtb. LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters. We also demonstrate that Mce1 functions as an important fatty acid transporter in Mtb and we determine that the integration of cholesterol and fatty acid transport by LucA is required for full bacterial virulence in vivo . These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key role for LucA in coordinating both transport activities.

Assimilation (phonology)

10.1101/121780

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Citations (0)

The genetic requirements of fatty acid import by Mycobacterium tuberculosis within macrophages

eLife (2019)

Evgeniya V. Nazarova Christine R. Montague Lu Huang Thuy La David G. Russell

Mycobacterium tuberculosis (Mtb) imports and metabolizes fatty acids to maintain infection within human macrophages. Although this is a well-established paradigm, the bacterial factors required for fatty acid import are poorly understood. Previously, we found that LucA and Mce1 are required for fatty acid import in Mtb (Nazarova et al., 2017). Here, we identified additional Mtb mutants that have a reduced ability to import a fluorescent fatty acid substrate during infection within macrophages. This screen identified the novel genes as rv2799 and rv0966c as be necessary for fatty acid import and confirmed the central role for Rv3723/LucA and putative components of the Mce1 fatty acid transporter (Rv0200/OmamB, Rv0172/Mce1D, and Rv0655/MceG) in this process.

Fatty acid synthesis

10.7554/elife.43621

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Citations (66)