Parameswaran Ramakrishnan obtained his BSc in 1993 and MSc in Biotechnology in 1996 from Mahatma Gandhi University, India. Later, he worked in an Indo-Swiss collaborative project studying the genome diversity in Mycobacterium leprae in the Department of Biotechnology, Madurai Kamaraj University, India, until the end of 1999.
PhD and Postdoc in Weizmann Institute of Science, Israel
In December 1999, he joined Weizmann Institute of Science, Israel, for his research toward
PhD under the guidance of Prof. David Wallach. He studied signal transduction in the immune system with a focus on mechanisms involved in the regulation and function of the protein NF-κB inducing kinase and obtained PhD in 2006. He continued in the same lab as a postdoctoral fellow and studied ubiquitination and proteasomal degradation of molecules in the NF-κB signaling pathway till the end of 2007. He also obtained 9 international patents on various inventions that emerged from his graduate and postdoctoral work at Weizmann
Institute of Science.
Postdoc in California Institute of Technology, United States
In January 2008, Dr. Ramakrishnan joined the lab of Nobel Laureate Prof. David Baltimore in the Department of Biology at California Institute of Technology. While in Baltimore lab, Dr. Ramakrishnan studied the regulation of NF-κB activation and T cell survival by glucose and identified the role of unique intracellular glycosylation called O-GlcNAcylation in NF-kB activation in T cells. He also discovered the role of the RNA-binding protein, Sam68, as an adaptor in proinflammatory signaling by TNF. Both of these findings are patented and are
active areas of current investigation. Dr. Ramakrishnan joined Case Western Reserve University's Department of Pathology as an Assistant Professor in Immunology in July 2013.
Dr. Ramakrishnan's lab focuses on signal transduction in autoimmunity and inflammation as well as immunometabolism. Studies involve cellular and molecular approaches, animal models and patient samples as well as collaborations with chemists aimed at drug discovery. Diseases of research interest are:
- Type 1 diabetes
- Inflammation-induced colon cancer
NF-κB is known to be a family of dimeric transcription factor that act as a key regulator of the immune and inflammatory responses. Because inflammation has been linked to so many diseases in recent times, there is much interest in the role of NF-κB in autoimmune conditions like diabetes and cancer.
Regulation of NF-κB activity by O-GlcNAc glycosylation and its role in diabetes
Significance: NF-κB is a preformed protein and its activation is dependent on posttranslational regulations. O-GlcNAcylation is a reversible intracellular protein modification whose levels are affected by glucose and other signals. Both O-GlcNAcylation and NF-κB activation has been associated in several physiological and pathological conditions including experimental and clinical diabetes, yet a direct link between them is missing and glycosylation of NF-κB by O-GlcNAcylation in diabetes remains poorly defined.
This project will identify O-GlcNAcylated NF-κB proteins, the site(s) of modification and study this process both structurally and functionally, under physiological and pathological conditions. Studies will also include generation of transgenic and knockout mouse models to determine the in vivo role of O-GlcNAcylation of NF-κB.
Role of Sam68 in chronic inflammatory signaling and cancer
Significance: We discovered that Sam68 plays crucial role in innate immune and apoptotic signaling by TNF. This finding links Sam68 function in inflammatory and autoimmune diseases as well as inflammation-induced cancer where deregulated TNF signaling is implicated.
This project aims to understand the molecular determinants of Sam68 function and its role in inflammatory signaling and cancer. The study will also delineate the physiological role of Sam68 in vivo in the immune system and elucidate its RNA binding independent functions.
de Jesùs TJ*, Tomalka J*, Centore J*, Staback FD, Agarwal R, Kern T, and Ramakrishnan P (2020). Negative Regulation of FOXP3 expression by c-Rel O-GlcNAcylation. Glycobiology (in revision)
Farabaugh KT, Krokowski D, Guan BJ, Gao Z, Gao XH, Wu J, Jobava R, Ray G, de Jesùs TJ, Bianchi MG, Chukwurah E, Bussolati O, Kilberg M, Buchner DA, Sen GC, Cotton C, McDonald C, Longworth M, Ramakrishnan P*, Hatzoglou M (2020). PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation. Elife. 2020 Mar 16;9. pii: e52241. doi: 10.7554/eLife.52241. PMID: 32175843; PMCID: PMC7145421. *Co-corresponding author
Basavarajappa SC, Ramakrishnan P (2020). Regulation of B-cell function by NF-kappaB c-Rel in health and disease. Cell Mol Life Sci. 2020 Mar 4. doi: 10.1007/s00018-020-03488-w. [Epub ahead of print] Review. PMID: 32130429
de Jesùs TJ, Ramakrishnan P (2020). NF-kB c-Rel dictates the inflammatory threshold by acting as a transcriptional repressor. iScience. 2020 Mar 27;23(3):100876. doi: 10.1016/j.isci.2020.100876. Epub 2020 Feb 1. PMID: 32062419; PMCID: PMC7031323
de Jesùs TJ , Centore JT, Ramakrishnan P (2019). Differential regulation of basal expression of inflammatory genes by NF-κB family subunits. Cell Mol Immunol. 2019 Aug;16(8):720-723. doi: 10.1038/s41423-019-0242-0. Epub 2019 May 29. PMID:31142799; PMCID: PMC6804592
Asthana A, Ramakrishnan P, Vicioso Y, Zhang K, Parameswaran R (2018). Hexosamine biosynthetic pathway inhibition leads to AML cell differentiation and cell death. Mol Cancer Ther. 2018 Oct;17(10):2226-2237. doi: 10.1158/1535-7163.MCT-18-0426. Epub 2018 Aug 6. PMID: 30082471; PMCID: PMC6168390
de Jesùs T, Shukla S, Ramakrishnan P (2018). Too sweet to resist: Control of immune cell function by O-GlcNAcylation. Cell Immunol. 2018 Nov;333:85-92. doi: 10.1016/j.cellimm.2018.05.010. Epub 2018 Jun 2. Review. PMID: 29887419; PMCID: PMC6275141.
Farabaugh KT, Majumder M, Guan BJ, Jobava R, Wu J, Krokowski D, Gao XH, Schuster A, Longworth M, Chan ED, Bianchi M, Dey M, Koromilas AE, Ramakrishnan P*, Hatzoglou M (2017). Protein kinase R mediates the inflammatory response induced by hyperosmotic stress. Mol Cell Biol. 2017 Feb 1;37(4). pii: e00521-16. doi: 10.1128/MCB.00521-16. Print 2017 Feb 15. PMID: 27920257; PMCID: PMC5288580. *Co-corresponding author
Tomalka J, de Jesùs TJ, Ramakrishnan P*. (2016). Sam68 is a Regulator of Toll Like Receptor Signaling. Cell Mol Immunol. Cell Mol Immunol. 2017 Jan;14(1):107-117. doi: 10.1038/cmi.2016.32. Epub 2016 Jul 4. PMID: 27374795.
Ramakrishnan P*, Yui M, Tomalka J, Majumdar D, Parameswara R, Baltimore D (2016). Deficiency of NF-kappaB c-Rel accelerates the development of autoimmune diabetes in non obese diabetic mice. Diabetes. 2016 Aug;65(8):2367-79. doi: 10.2337/db15-1607. Epub 2016 May 23. PMID: 27217485. *Co-corresponding author.
Parameswaran R, Ramakrishnan P, De Lima M, Lee DA, Moreton S and Wald DN. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nature Communications. Nat Commun. 2016 Apr 4;7:11154. doi: 10.1038/ncomms11154, PMID: 27040177; PMCID: PMC4822012
de Jesùs TJ and Ramakrishnan P* (2015). Sugar-Coating the Skin. Austin Journal of Clinical Pathology. 2015 Nov; 2(3): 1035.
So AY, Chaudhuri A, Sookram R, Minisandram A, Cheng D, Xie C, Lim L, Garcia Flores Y, Jiang S, Keown C, Ramakrishnan P, Baltimore D (2014). Dual mechanisms by which mir-125b represses IRF4 to cause myeloid and B-cell Leukemia. Blood. 2014 Aug 28;124(9):1502-12. doi: 10.1182/blood-2014-02-553842. Epub 2014 Jul 8. PMID: 25006123; PMCID: PMC4148772
Ramakrishnan P, Clark PM, Mason DE, Peters ED, Hsieh-Wilson LC and Baltimore D (2013). Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation. Science Signaling, August 27. Vol 6 Issue 290 ra75.
Yang L, Boldi MP, Yu Y, Liu CS, Ea CK, Ramakrishnan P, Taganov KD, Zhao JL and Baltimore D (2012). miR-146a control of the resolution of T cell responses in mice. J Exp Med. Aug 27;209(9):1655-70.
Raskatov JA, Meier JL, Puckett JW, Yang F, Ramakrishnan P, and Dervan PB (2012). Modulation of NF-κB Dependent Gene Transcription Using Programmable DNA Minor Groove Binders. Proc Natl Acad Sci U S A. Jan 24;109(4):1023-8.
Ramakrishnan P, Baltimore D (2011). Sam68 is Required for both NF-κB Activation and Apoptosis Signaling by the TNF receptor. Molecular Cell, Jul 22;43(2):167-79.
Ramakrishnan P, Kahn D, Baltimore D (2011). Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells. Cell Death and Differentiation, April;18(4):690-9.
Citri A, Harari D, Shohat G, Ramakrishnan P, Gan J, Lavi S, Eisenstein M, Kimchi A, Wallach D, Pietrokovski S, Yarden Y (2006). Hsp90 recognizes a common surface on client kinases. J Biol Chem. May 19;281(20):14361-9.
Sanchez-Valdepenas C, Martin AG, Ramakrishnan P, Wallach D, Fresno M (2006). NF-κB-inducing kinase is involved in the activation of the CD28 responsive element through phosphorylation of c-Rel and regulation of its transactivating activity. J Immunol. Apr 15;176(8):4666-74.
Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H (2005). TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-κB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci U S A 102, 2874-2879.
Ramakrishnan P, Wang W, Wallach D (2004). Receptor-specific signaling for both the alternative and the canonical NF-κB activation pathways by NF-κB-inducing kinase. Immunity 21, 477-489.
Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D (2004). Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173, 2976-2984.