Inositol Metabolite Depletion Induces Hallmarks of ER Stress Without Activating the UPR

Authors

  • Shreyas Chakravarty The Harker School
  • Arianna Broad Weill Institute for Cell and Molecular Biology, Cornell University

DOI:

https://doi.org/10.47611/jsrhs.v13i4.7708

Keywords:

Unfolded Protein Response, Inositol, Endoplasmic Reticulum, Reactive Oxygen Species, Membrane Aberrancy, Phosphoinositide, Membrane Stress, Redox Stress, ER Stress

Abstract

The unfolded protein response (UPR) is a transcriptional pathway that responds to unfolded proteins in the endoplasmic reticulum (ER) through three well-defined pathways. However, the production of reactive oxygen species (ROS), membrane aberrancy, and the depletion of the sugar, lipid component, and signaling molecule inositol are also linked to UPR activation. While the mechanism for ROS-mediated UPR activation is understood, the mechanism for membrane aberrancy and inositol depletion—believed to be the same—is much less clear. Given inositol depletion’s reduction of several inositol metabolites with divergent roles in the UPR, our study of the transcriptomic changes due to the metabolic depletion of certain inositols attempts to illuminate the poorly understood connections between inositol depletion, membrane aberrancy, and the UPR. We amalgamated and filtered RNA sequencing data from 19 studies knocking out inositol metabolic enzymes and conducted functional analyses. Our results indicated that while protein degradation, membrane stress, and redox stress—all hallmarks of ER stress and heavily associated with the UPR—were transcriptionally supported by inositol metabolite depletion, the UPR was not activated. As a result, inositol depletion studies could carry a confounding noise due to the depletion of inositol products that obfuscates attempts to define inositol’s connections with membrane aberrancy and the UPR. The results of our study urge further research into the consequences of inositol metabolite depletion both to vitiate the resulting concerns about inositol depletion studies and to explain the lack of UPR activation even with the induction of ER stress hallmarks associated with UPR activation.

Downloads

Download data is not yet available.

References or Bibliography

Balla T. (2013). Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiological reviews, 93(3), 1019–1137. https://doi.org/10.1152/physrev.00028.2012

Benjamin, B., Goldgur, Y., Jork, N., Jessen, H. J., Schwer, B., & Shuman, S. (2022). Structures of fission yeast inositol pyrophosphate kinase asp1 in ligand-free, substrate-bound, and product-bound states. MBio, 13(6). https://doi.org/10.1128/mbio.03087-22

Bissaro, B., Várnai, A., Røhr, Å. K., & Eijsink, V. G. H. (2018). Oxidoreductases and reactive oxygen species in conversion of lignocellulosic biomass. Microbiology and Molecular Biology Reviews, 82(4). https://doi.org/10.1128/mmbr.00029-18

Burke, J. E., Triscott, J., Emerling, B. M., & Hammond, G. R. V. (2022). Beyond pi3ks: Targeting phosphoinositide kinases in disease. Nature Reviews Drug Discovery, 22(5), 357-386. https://doi.org/10.1038/s41573-022-00582-5

Campos, C. B. de, Zhu, Y. X., Sepetov, N., Romanov, S., Bruins, L. A., Shi, C.-X., Stein, C. K., Petit, J. L., Polito, A. N., Sharik, M. E., Meermeier, E. W., Ahmann, G. J., Armenta, I. D. L., Kruse, J., Bergsagel, P. L., Chesi, M., Meurice, N., Braggio, E., & Stewart, A. K. (2019). Identification of pikfyve kinase as a target in multiple myeloma. Haematologica, 105(6), 1641-1649. https://doi.org/10.3324/haematol.2019.222729

Cheung, S. K. K., Kwok, J., Or, P. M. Y., Wong, C. W., Feng, B., Choy, K. W., Chang, R. C. C., Burbach, J. P. H., Cheng, A. S. L., & Chan, A. M. (2023). Neuropathological signatures revealed by transcriptomic and proteomic analysis in pten-deficient mouse models. Scientific Reports, 13(1). https://doi.org/10.1038/s41598-023-33869-7

Cox, J. S., Chapman, R. E., & Walter, P. (1997). The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane. Molecular biology of the cell, 8(9), 1805–1814. https://doi.org/10.1091/mbc.8.9.1805

De Block, J., Szopinska, A., Guerriat, B., Dodzian, J., Villers, J., Hochstenbach, J.-F., & Morsomme, P. (2015). The yeast pmp3p has a significant role in plasma membrane organization. Journal of Cell Science. https://doi.org/10.1242/jcs.173211

Deranieh, Rania M., and Miriam L. Greenberg. “Cellular Consequences of Inositol Depletion.” Biochemical Society Transactions, vol. 37, no. 5, 21 Sept. 2009, pp. 1099-103, https://doi.org/10.1042/bst0371099

Deranieh, R. M., He, Q., Caruso, J. A., & Greenberg, M. L. (2013). Phosphorylation regulates myo-Inositol-3-phosphate synthase. Journal of Biological Chemistry, 288(37), 26822-26833. https://doi.org/10.1074/jbc.m113.479121

De-Souza, E. A., Pimentel, F. S. A., Machado, C. M., Martins, L. S., da-Silva, W. S., Montero-Lomelí, M., & Masuda, C. A. (2013). The unfolded protein has a protective role in yeast models of classic galactosemia. Models & Mechanisms. https://doi.org/10.1242/dmm.012641

Dhandayuthapani, S., Jagannath, C., Nino, C., Saikolappan, S., & Sasindran, S. J. (2009). Methionine sulfoxide reductase B (MsrB) of mycobacterium smegmatis plays a limited role in resisting oxidative stress. Tuberculosis, 89, S26-S32. https://doi.org/10.1016/s1472-9792(09)70008-3

Falkenburger, B. H., Jensen, J. B., Dickson, E. J., Suh, B. C., & Hille, B. (2010). Phosphoinositides: lipid regulators of membrane proteins. The Journal of physiology, 588(Pt 17), 3179–3185. https://doi.org/10.1113/jphysiol.2010.192153

Figueiredo, J., Dias, W., Mendonça-Previato, L., Previato, J., & Heise, N. (2005). Characterization of the inositol phosphorylceramide synthase activity from Trypanosoma cruzi. Biochemical Journal, 387(2), 519-529. https://doi.org/10.1042/bj20041842

Fradet, A., & Fitzgerald, J. (2016). INPPL1 gene mutations in opsismodysplasia. Journal of Human Genetics, 62(2), 135-140. https://doi.org/10.1038/jhg.2016.119

Halbleib, K., Pesek, K., Covino, R., Hofbauer, H. F., Wunnicke, D., Hänelt, I., Hummer, G., & Ernst, R. (2017). Activation of the Unfolded Protein Response by Lipid Bilayer Stress. Molecular cell, 67(4), 673–684.e8. https://doi.org/10.1016/j.molcel.2017.06.012

Harbauer, A. B., Hees, J. T., Wanderoy, S., Segura, I., Gibbs, W., Cheng, Y., Ordonez, M., Cai, Z., Cartoni, R., Ashrafi, G., Wang, C., Perocchi, F., He, Z., & Schwarz, T. L. (2022). Neuronal mitochondria transport pink1 mRNA via synaptojanin 2 to support local mitophagy. Neuron, 110(9), 1516-1531.e9. https://doi.org/10.1016/j.neuron.2022.01.035

Hasegawa, J., Strunk, B. S., & Weisman, L. S. (2017). PI5P and PI(3,5)P2: Minor, but essential phosphoinositides. Cell Structure and Function, 42(1), 49-60. https://doi.org/10.1247/csf.17003

Heaver, S. L., Le, H. H., Tang, P., Baslé, A., Mirretta Barone, C., Vu, D. L., Waters, J. L., Marles-Wright, J., Johnson, E. L., Campopiano, D. J., & Ley, R. E. (2022). Characterization of inositol lipid metabolism in gut-associated bacteroidetes. Nature Microbiology, 7(7), 986-1000. https://doi.org/10.1038/s41564-022-01152-6

Higgins, R., Gendron, J., Rising, L., Mak, R., Webb, K., Kaiser, S., Zuzow, N., Riviere, P., Yang, B., Fenech, E., Tang, X., Lindsay, S., Christianson, J., Hampton, R., Wasserman, S., & Bennett, E. (2015). The unfolded protein response triggers site-specific regulatory ubiquitylation of 40S ribosomal proteins. Molecular Cell, 59(1), 35-49. https://doi.org/10.1016/j.molcel.2015.04.026

Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2008). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4(1), 44-57. https://doi.org/10.1038/nprot.2008.211

Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., Saito, T., Saido, T. C., Ikezu, T., Takai, T., Sasaki, T., & Tomita, T. (2023). INPP5D modulates trem2 loss-of-function phenotypes in a β-amyloidosis mouse model. IScience, 26(4), 106375. https://doi.org/10.1016/j.isci.2023.106375

Iyer, J., Singh, M. D., Jensen, M., Patel, P., Pizzo, L., Huber, E., Koerselman, H., Weiner, A. T., Lepanto, P., Vadodaria, K., Kubina, A., Wang, Q., Talbert, A., Yennawar, S., Badano, J., Manak, J. R., Rolls, M. M., Krishnan, A., & Girirajan, S. (2018). Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in drosophila melanogaster. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-04882-6

Jadhav, S., Russo, S., Cottier, S., Schneiter, R., Cowart, A., & Greenberg, M. L. (2016). Valproate Induces the Unfolded Protein Response by Increasing Ceramide Levels. The Journal of biological chemistry, 291(42), 22253–22261. https://doi.org/10.1074/jbc.M116.752634

Jesch, S. A., Zhao, X., Wells, M. T., & Henry, S. A. (2005). Genome-wide analysis reveals inositol, not choline, as the major effector of ino2p-ino4p and unfolded protein response target gene expression in yeast. Journal of Biological Chemistry, 280(10), 9106-9118. https://doi.org/10.1074/jbc.m411770200

Kader, J.-C. (1996). Lipid-transfer proteins in plants. Annual Review of Plant Physiology and Plant Molecular Biology, 47(1), 627-654. https://doi.org/10.1146/annurev.arplant.47.1.627

Karagöz, G. E., Acosta-Alvear, D., & Walter, P. (2019). The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum. Cold Spring Harbor perspectives in biology, 11(9), a033886. https://doi.org/10.1101/cshperspect.a033886

Kim, Y. J., Hernandez, M. L., & Balla, T. (2013). Inositol lipid regulation of lipid transfer in specialized membrane domains. Trends in cell biology, 23(6), 270–278. https://doi.org/10.1016/j.tcb.2013.01.009

Kolberg, L., Raudvere, U., Kuzmin, I., Adler, P., Vilo, J., & Peterson, H. (2023). G:Profiler—interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Research, 51(W1), W207-W212. https://doi.org/10.1093/nar/gkad347

Ladewig, E., Michelini, F., Jhaveri, K., Castel, P., Carmona, J., Fairchild, L., Zuniga, A. G., Arruabarrena-Aristorena, A., Cocco, E., Blawski, R., Kittane, S., Zhang, Y., Sallaku, M., Baldino, L., Hristidis, V., Chandarlapaty, S., Abdel-Wahab, O., Leslie, C., Scaltriti, M., & Toska, E. (2022). The oncogenic pi3k-induced transcriptomic landscape reveals key functions in splicing and gene expression regulation. Cancer Research, 82(12), 2269-2280. https://doi.org/10.1158/0008-5472.can-22-0446

Lajoie, P., Moir, R. D., Willis, I. M., & Snapp, E. L. (2012). Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells. Molecular biology of the cell, 23(5), 955–964. https://doi.org/10.1091/mbc.E11-12-0995

Li, G., Wu, Y., Zhang, Y., Wang, H., Li, M., He, D., Guan, W., & Yao, H. (2024). Research progress on phosphatidylinositol 4-kinase inhibitors. Biochemical Pharmacology, 220, 115993. https://doi.org/10.1016/j.bcp.2023.115993

López-Ribera, I., La Paz, J. L., Repiso, C., García, N., Miquel, M., Hernández, M. L., Martínez-Rivas, J. M., & Vicient, C. M. (2014). The evolutionary conserved oil body associated protein obap1 participates in the regulation of oil body size. Plant Physiology, 164(3), 1237-1249. https://doi.org/10.1104/pp.113.233221

Lykidis, A., Jackson, P. D., Rock, C. O., & Jackowski, S. (1997). The role of cdp-diacylglycerol synthetase and phosphatidylinositol synthase activity levels in the regulation of cellular phosphatidylinositol content. Journal of Biological Chemistry, 272(52), 33402-33409. https://doi.org/10.1074/jbc.272.52.33402

Maag, D., Maxwell, M. J., Hardesty, D. A., Boucher, K. L., Choudhari, N., Hanno, A. G., Ma, J. F., Snowman, A. S., Pietropaoli, J. W., Xu, R., Storm, P. B., Saiardi, A., Snyder, S. H., & Resnick, A. C. (2011). Inositol polyphosphate multikinase is a physiologic pi3-kinase that activates akt/pkb. Proceedings of the National Academy of Sciences, 108(4), 1391-1396. https://doi.org/10.1073/pnas.1017831108

Maekawa, M., Terasaka, S., Mochizuki, Y., Kawai, K., Ikeda, Y., Araki, N., Skolnik, E. Y., Taguchi, T., & Arai, H. (2014). Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis. Proceedings of the National Academy of Sciences, 111(11). https://doi.org/10.1073/pnas.1311029111

Malek, M., Kielkowska, A., Chessa, T., Anderson, K. E., Barneda, D., Pir, P., Nakanishi, H., Eguchi, S., Koizumi, A., Sasaki, J., Juvin, V., Kiselev, V. Y., Niewczas, I., Gray, A., Valayer, A., Spensberger, D., Imbert, M., Felisbino, S., Habuchi, T., . . . Stephens, L. R. (2017). PTEN regulates pi(3,4)p2 signaling downstream of class I pi3k. Molecular Cell, 68(3), 566-580.e10. https://doi.org/10.1016/j.molcel.2017.09.024

Mansat, M., Kpotor, A. O., Chicanne, G., Picot, M., Mazars, A., Flores-Flores, R., Payrastre, B., Hnia, K., & Viaud, J. (2024). MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion. Proceedings of the National Academy of Sciences, 121(23). https://doi.org/10.1073/pnas.2217971121

Mayer, M. P., & Bukau, B. (2005). Hsp70 chaperones: Cellular functions and molecular mechanism. Cellular and Molecular Life Sciences, 62(6). https://doi.org/10.1007/s00018-004-4464-6

Mielich-Süss, B., Schneider, J., & Lopez, D. (2013). Overproduction of flotillin influences cell differentiation and shape in bacillus subtilis. MBio, 4(6). https://doi.org/10.1128/mbio.00719-13

Naik, S., Wood, A. R., Ongenaert, M., Saidiyan, P., Elstak, E. D., Lanz, H. L., Stallen, J., Janssen, R., Smythe, E., & Erdmann, K. S. (2021). A 3D renal proximal tubule on chip model phenocopies lowe syndrome and dent II disease tubulopathy. International Journal of Molecular Sciences, 22(10), 5361. https://doi.org/10.3390/ijms22105361

Paranagama, M. P., Sakamoto, K., Amino, H., Awano, M., Miyoshi, H., & Kita, K. (2010). Contribution of the FAD and quinone binding sites to the production of reactive oxygen species from ascaris suum mitochondrial complex II. Mitochondrion, 10(2), 158-165. https://doi.org/10.1016/j.mito.2009.12.145

Posor, Y., Jang, W. & Haucke, V. Phosphoinositides as membrane organizers. (2022). Nat Rev Mol Cell Biol 23, 797–816. https://doi.org/10.1038/s41580-022-00490-x

Promlek, T., Ishiwata-Kimata, Y., Shido, M., Sakuramoto, M., Kohno, K., & Kimata, Y. (2011). Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Molecular biology of the cell, 22(18), 3520–3532. https://doi.org/10.1091/mbc.E11-04-0295

Poxleitner, M., Rogers, S. W., Lacey Samuels, A., Browse, J., & Rogers, J. C. (2006). A role for caleosin in degradation of oil‐body storage lipid during seed germination. The Plant Journal, 47(6), 917-933. https://doi.org/10.1111/j.1365-313x.2006.02845.x

Qin, L., Zhou, Z., Li, Q., Zhai, C., Liu, L., Quilichini, T. D., Gao, P., Kessler, S. A., Jaillais, Y., Datla, R., Peng, G., Xiang, D., & Wei, Y. (2020). Specific recruitment of phosphoinositide species to the plant-pathogen interfacial membrane underlies arabidopsis susceptibility to fungal infection. The Plant Cell, 32(5), 1665-1688. https://doi.org/10.1105/tpc.19.00970

Ramos, A. R., Ghosh, S., & Erneux, C. (2019). The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease. Journal of Lipid Research, 60(2), 276-286. https://doi.org/10.1194/jlr.r087908

Radanović, T., & Ernst, R. (2021). The Unfolded Protein Response as a Guardian of the Secretory Pathway. Cells, 10(11), 2965. https://doi.org/10.3390/cells10112965

Reich, S., Nguyen, C. D. L., Has, C., Steltgens, S., Soni, H., Coman, C., Freyberg, M., Bichler, A., Seifert, N., Conrad, D., Knobbe-Thomsen, C. B., Tews, B., Toedt, G., Ahrends, R., & Medenbach, J. (2020). A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-16747-y

Rouillard, A. D., Gundersen, G. W., Fernandez, N. F., Wang, Z., Monteiro, C. D., McDermott, M. G., & Ma'ayan, A. (2016). The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database, 2016, baw100. https://doi.org/10.1093/database/baw100

Sanchez, A. M., Garg, A., Shuman, S., & Schwer, B. (2019). Inositol pyrophosphates impact phosphate homeostasis via modulation of RNA 3′ processing and transcription termination. Nucleic Acids Research, 47(16), 8452-8469. https://doi.org/10.1093/nar/gkz567

Sarikaya, E., Sabha, N., Volpatti, J., Pannia, E., Maani, N., Gonorazky, H. D., Celik, A., Liang, Y., Onofre-Oliveira, P., & Dowling, J. J. (2022). Natural history of a mouse model of x-linked myotubular myopathy. Disease Models & Mechanisms, 15(7). https://doi.org/10.1242/dmm.049342

Shamu, Caroline E., et al. “The Unfolded-protein-response Pathway in Yeast.” Trends in Cell Biology, vol. 4, no. 2, Feb. 1994, pp. 56-60. Science Direct, https://doi.org/10.1016/0962-8924(94)90011-6

Schaffer, W. M., & Bronnikova, T. V. (2012). Peroxidase-ROS interactions. Nonlinear Dynamics, 68(3), 413-430. https://doi.org/10.1007/s11071-011-0314-x

Sherman, B. T., Hao, M., Qiu, J., Jiao, X., Baseler, M. W., Lane, H. C., Imamichi, T., & Chang, W. (2022). DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Research, 50(W1), W216-W221. https://doi.org/10.1093/nar/gkac194

Shimada, T. L., & Hara-Nishimura, I. (2010). Oil-Body-Membrane proteins and their physiological functions in plants. Biological and Pharmaceutical Bulletin, 33(3), 360-363. https://doi.org/10.1248/bpb.33.360

Snapp, E. (2012). Unfolded Protein Responses With or Without Unfolded Proteins? Cells, 1(4), 926–950. MDPI AG. Retrieved from http://dx.doi.org/10.3390/cells1040926

Starodubtseva, A., Kalachova, T., Retzer, K., Jelínková, A., Dobrev, P., Lacek, J., Pospíchalová, R., Angelini, J., Guivarc'h, A., Pateyron, S., Soubigou-Taconnat, L., Burketová, L., & Ruelland, E. (2022). An arabidopsis mutant deficient in phosphatidylinositol-4-phosphate kinases ß1 and ß2 displays altered auxin-related responses in roots. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-10458-8

Su, C., Rodriguez-Franco, M., Lace, B., Nebel, N., Hernandez-Reyes, C., Liang, P., Schulze, E., Mymrikov, E. V., Gross, N. M., Knerr, J., Wang, H., Siukstaite, L., Keller, J., Libourel, C., Fischer, A. A. M., Gabor, K. E., Mark, E., Popp, C., Hunte, C., . . . Ott, T. (2023). Stabilization of membrane topologies by proteinaceous remorin scaffolds. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-35976-5

Suliman, M., Case, K. C., Schmidtke, M. W., Lazcano, P., Onu, C. J., Greenberg, M. L. (2022). “Inositol Depletion Regulates Phospholipid Metabolism and Activates Stress Signaling in HEK293T Cells.” BioRXiv, https://doi.org/10.1101/2022.02.21.481362

Termini, C. M., & Gillette, J. M. (2017). Tetraspanins function as regulators of cellular signaling. Frontiers in Cell and Developmental Biology, 5. https://doi.org/10.3389/fcell.2017.00034

Travers, K. J., Patil, C. K., Wodicka, L., Lockhart, D. J., Weissman, J. S., & Walter, P. (2000). Functional and genomic analyses reveal an essential coordination between the unfolded protein response and er-associated degradation. Cell, 101(3), 249-258. https://doi.org/10.1016/s0092-8674(00)80835-1

The Uniprot Consortium, Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Ahmad, S., Alpi, E., Bowler-Barnett, E. H., Britto, R., Bye-A-Jee, H., Cukura, A., Denny, P., Dogan, T., Ebenezer, T., Fan, J., Garmiri, P., Gonzales, L. J. D. C., Hatton-Ellis, E., Hussein, A., . . . Lussi, Y. (2022). UniProt: The universal protein knowledgebase in 2023. Nucleic Acids Research, 51(D1), D523-D531. https://doi.org/10.1093/nar/gkac1052

Veith, A., & Moorthy, B. (2018). Role of cytochrome p450s in the generation and metabolism of reactive oxygen species. Current Opinion in Toxicology, 7, 44-51. https://doi.org/10.1016/j.cotox.2017.10.003

Volmer, R., van der Ploeg, K., & Ron, D. (2013). Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proceedings of the National Academy of Sciences of the United States of America, 110(12), 4628–4633. https://doi.org/10.1073/pnas.1217611110

Watt, M. E. van der, Reader, J., Churchyard, A., Nondaba, S. H., Lauterbach, S. B., Niemand, J., Abayomi, S., van Biljon, R. A., Connacher, J. I., van Wyk, R. D. J., Le Manach, C., Paquet, T., González Cabrera, D., Brunschwig, C., Theron, A., Lozano-Arias, S., Rodrigues, J. F. I., Herreros, E., Leroy, D., . . . Birkholtz, L.-M. (2018). Potent plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials. Journal of Antimicrobial Chemotherapy, 73(5), 1279-1290. https://doi.org/10.1093/jac/dky008

Wei, W., Geer, M. J., Guo, X., Dolgalev, I., Sanjana, N. E., & Neel, B. G. (2023). Genome-wide crispr/cas9 screens reveal shared and cell-specific mechanisms of resistance to shp2 inhibition. Journal of Experimental Medicine, 220(5). https://doi.org/10.1084/jem.20221563

Yang, A. K. M. S. G.-Y., & Shamsuddin, A. K. M. (2015). Inositol & its phosphates: Basic science to practical applications. Bentham Science. https://doi.org/10.2174/97816810800791150101

Ying, J. F., Lu, Z. B., Fu, L. Q., Tong, Y., Wang, Z., Li, W. F., & Mou, X. Z. (2021). The role of iron homeostasis and iron-mediated ROS in cancer. American journal of cancer research, 11(5), 1895–1912. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8167679/

Yu, W., Daniel, J., Mehta, D., Maddipati, K. R., & Greenberg, M. L. (2017). MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate. PloS one, 12(8), e0182534. https://doi.org/10.1371/journal.pone.0182534

Yuk, C. M., Kim, D., Hong, S., Kim, M., Jeong, H.-W., Park, S. J., Min, H., Kim, W., Kim, S.-G., Seong, R. H., Kim, S., & Lee, S.-H. (2024). Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling. BioRχiv. https://doi.org/10.1101/2024.01.08.574595

Zhang, M., Suarez, E., Vasquez, J. L., Nathanson, L., Peterson, L. E., Rajapakshe, K., Basil, P., Weigel, N. L., Coarfa, C., & Agoulnik, I. U. (2018). Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity. Oncogene, 38(7), 1121-1135. https://doi.org/10.1038/s41388-018-0498-3

Zylstra, A., Hadj-Moussa, H., Horkai, D., Whale, A. J., Piguet, B., & Houseley, J. (2023). Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation. PLOS Biology, 21(8), e3002250. https://doi.org/10.1371/journal.pbio.3002250

Published

11-30-2024

How to Cite

Chakravarty, S., & Broad, A. (2024). Inositol Metabolite Depletion Induces Hallmarks of ER Stress Without Activating the UPR. Journal of Student Research, 13(4). https://doi.org/10.47611/jsrhs.v13i4.7708

Issue

Section

HS Research Projects