Stanford Advisors

All Publications

  • PACT Establishes a Post-transcriptional Brake on Mitochondrial Biogenesis by Promoting the Maturation of miR-181c. The Journal of biological chemistry Dogan, A. E., Hamid, S. M., Yildirim, A. D., Yildirim, Z., Sen, G., Riera, C. E., Gottlieb, R. A., Erbay, E. 2022: 102050


    The double-stranded RNA-dependent protein kinase (PKR) activating protein (PACT), an RNA-binding protein (RNAbp) that is part of the RNA-induced silencing complex (RISC), plays a key role in microRNA (miR)-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RISC, and determines proper miR length. Apart from PACT's role in mediating the anti-viral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a post-transcriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial Complex IV subunit I (Mtco1) and Sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.

    View details for DOI 10.1016/j.jbc.2022.102050

    View details for PubMedID 35598827

  • Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression EMBO MOLECULAR MEDICINE Yildirim, Z., Baboo, S., Hamid, S. M., Dogan, A. E., Tufanli, O., Robichaud, S., Emerton, C., Diedrich, J. K., Vatandaslar, H., Nikolos, F., Gu, Y., Iwawaki, T., Tarling, E., Ouimet, M., Nelson, D. L., Yates, J. R., Walter, P., Erbay, E. 2022: e15344


    Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.

    View details for DOI 10.15252/emmm.202115344

    View details for Web of Science ID 000758718600001

    View details for PubMedID 35191199

  • S-Adenosylmethionine Inhibits La Ribonucleoprotein Domain Family Member 1 in Murine Liver and Human Liver Cancer Cells. Hepatology (Baltimore, Md.) Ramani, K., Robinson, A. E., Berlind, J., Fan, W., Abeynayake, A., Binek, A., Barbier-Torres, L., Noureddin, M., Nissen, N. N., Yildirim, Z., Erbay, E., Mato, J. M., Van Eyk, J. E., Lu, S. C. 2021


    BACKGROUND & AIMS: Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion, develop non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, the phosphos-proteome has not been characterized and whether they contribute to liver pathology is largely unknown. Our study aimed to fill this gap.APPROACH & RESULTS: We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found the most striking change was hyperphosphorylation and increased content of La-Related Protein 1 (LARP1), which in the unphosphorylated form negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in the KO livers. The translation of TOP mRNAs RPS3 and RPL18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a novel, SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1 overexpression mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC.CONCLUSION: Our results reveal a novel SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.

    View details for DOI 10.1002/hep.32130

    View details for PubMedID 34449924

  • Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth EMBO REPORTS Hamid, S., Citir, M., Terzi, E., Cimen, I., Yildirim, Z., Dogan, A., Kocaturk, B., Onat, U., Arditi, M., Weber, C., Traynor-Kaplan, A., Schultz, C., Erbay, E. 2020; 21 (12): e51462


    The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

    View details for DOI 10.15252/embr.202051462

    View details for Web of Science ID 000583773600001

    View details for PubMedID 33140520

    View details for PubMedCentralID PMC7726810

  • Double bond configuration of palmitoleate is critical for atheroprotection MOLECULAR METABOLISM Cimen, I., Yildirim, Z., Dogan, A., Yildirim, A., Tufanli, O., Onat, U., UyenThao Nguyen, Watkins, S. M., Weber, C., Erbay, E. 2019; 28: 58-72


    Saturated and trans fat consumption is associated with increased cardiovascular disease (CVD) risk. Current dietary guidelines recommend low fat and significantly reduced trans fat intake. Full fat dairy can worsen dyslipidemia, but recent epidemiological studies show full-fat dairy consumption may reduce diabetes and CVD risk. This dairy paradox prompted a reassessment of the dietary guidelines. The beneficial metabolic effects in dairy have been claimed for a ruminant-derived, trans fatty acid, trans-C16:1n-7 or trans-palmitoleate (trans-PAO). A close relative, cis-PAO, is produced by de novo lipogenesis and mediates inter-organ crosstalk, improving insulin-sensitivity and alleviating atherosclerosis in mice. These findings suggest trans-PAO may be a useful substitute for full fat dairy, but a metabolic function for trans-PAO has not been shown to date.Using lipidomics, we directly investigated trans-PAO's impact on plasma and tissue lipid profiles in a hypercholesterolemic atherosclerosis mouse model. Furthermore, we investigated trans-PAO's impact on hyperlipidemia-induced inflammation and atherosclerosis progression in these mice.Oral trans-PAO supplementation led to significant incorporation of trans-PAO into major lipid species in plasma and tissues. Unlike cis-PAO, however, trans-PAO did not prevent organelle stress and inflammation in macrophages or atherosclerosis progression in mice.A significant, inverse correlation between circulating trans-PAO levels and diabetes incidence and cardiovascular mortality has been reported. Our findings show that trans-PAO can incorporate efficiently into the same pools that its cis counterpart is known to incorporate into. However, we found trans-PAO's anti-inflammatory and anti-atherosclerotic effects are muted due to its different structure from cis-PAO.

    View details for DOI 10.1016/j.molmet.2019.08.004

    View details for Web of Science ID 000487684000006

    View details for PubMedID 31422082

    View details for PubMedCentralID PMC6822256

  • Periplasmic and extracellular production of cellulase from recombinant Escherichia coli cells JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY Yildirim, Z., Celik, E. 2017; 92 (2): 319-324

    View details for DOI 10.1002/jctb.5008

    View details for Web of Science ID 000396893400008