1.Molecular pathogenesis of HIV
In a factory, someone has to stand on the loading dock, checking the goods going out. By recognizing labels like bar codes on each shipment, the loading dock supervisor makes sure that the products get where they are supposed to go. A cell is like a factory: one of its most important jobs is to produce proteins, like transcription factors and nuclear transport receptors. But in cellular factories, the sorting task is complicated by the fact that proteins are used by the cell itself as well as delivered to outside “customers”. Scientists are succeeding at deciphering the cell’s complex bar-coding system. But, surprisingly, they have never managed to get at the loading dock itself to see how HIV genome is actually shipped to their destinations.
Regulation of HIV-1 infectivity and pathogenesis of AIDS remain central interests of the laboratory. Unlike the typical animal-oncoretroviruses, lentiviruses such as HIV have the ability to infect and replicate within non-cycling cells. Nucleo-cytoplasmic transport of the viral genome is vital for the replication and assembly of many viruses. Nuclear transport of Human immunodeficiency viral (HIV) genome, for instance, is critical for productive infection in non-dividing cells such as human macrophages. Our understanding on the nuclear import of HIV preintegration complexes into the nucleus of non-dividing cells remains rudimentary, and identification of cellular protein(s) which interact with viral PICs is eagerly awaited and will reveal cellular system that are important to diverse and basic cellular processes. Our laboratory will focus on two issues: mechanism of HIV PICs nuclear import, and signals in PICs that regulate its nuclear import. To achieve this goal we will clone and characterize the host genes that are involved in this process. We will also attempt to identify how the host genes interact with viral proteins to bring about the events of HIV pathogenesis. Furthermore, a better understanding of nuclear transport during viral infection might prove useful for designing antiviral therapies and for designing delivery vectors for gene therapy, which is a rapidly developing and increasingly important area of research in biomedical sciences.
Recent focus of the lab is to understand Indian subtype C HIV-1 envelope function during viral replication and to develop envelope based candidate vaccine for HIV-1/AIDS.
The imbalance in the signalling network regulating cellular functions including proliferation, differentiation and cell survival results in cancer. Our group aims to identify and characterize the factors that are important for immortalization and transformation of cells which are critical for tumorigenesis.
Ras proteins are well-known small GTPases and playing critical role in regulating cellular processes. In addition to the classical enzymatic effectors of Ras, non-enzymatic effectors grouped as “Ras-association domain containing family” (RASSF) proteins have been recently identified. The mechanism by which these proteins intercept tumor pathways is a key area of research in the lab.
Guanine nucleotide binding protein-like (GNL) – nuclear/nucleolar GTPases belong to the MMR1-HSR1 family of large putative GTPases which are emerging as crucial coordinators of signalling cascades in different cellular compartments. Members of this family are reported to regulate rRNA processing, ribosome biogenesis as well as cell cycle. GNLs are reported to be overexpressed in several cancers and there are emerging evidence from our and others lab implicating their roles in cancer progression. Functional characterization of GNLs in relation with tumorigenesis is another area of research in the lab.
- Professor, Department of Biotechnology, Indian Institute of Technology Madras, Chennai(May 2010- present)
- Associate Professor, Department of Biotechnology, Indian Institute of Technology Madras, Chennai(May 2007- May 2010).
- Staff Scientist-V, Centre DNA Fingerprinting and Diagnostics, Hyderabad(May 2005 – May 2007).
- Visiting Scientist, Institute of Molecular and Cellular Biology, Singapore(Aug-Dec. 2003).
- Visiting Scientist, University of Pittsburgh, Pittsburgh, USA(March-May 2002).
- Staff Scientist-IV, Centre DNA Fingerprinting and Diagnostics, Hyderabad(Oct 2000-April 2005).
- Research Associate, University of Alabama, Birmingham, USA(1997-00).
- Research Associate, University of Pennsylvania, Philadelphia, USA(1996-97).
- Postdoctoral Fellow, Thomas Jefferson Univ, Philadelphia, USA(1994-95).
- Prakash Singh S, Raja S, MahalingamS. (2019) LentiviralVpx induces alteration of mammalian cell nuclear envelope integrity. BiochemBiophys Res Commun. 2019 Mar 26;511(1):192-198. doi: 10.1016/j.bbrc.2019.02.018. Epub 2019 Feb 15.
- Ramachandran P, Balamurali D, Peter JJ, Kumar MM, Safwan M, Vij M, Rela M, Mahalingam (2019) RNA-seq reveals outcome-specific gene expression of MMP7 and PCK1 in biliary atresia. MolBiol Rep. 2019 Jul 24. doi: 10.1007/s11033-019-04969-3.
- Ananthi S, Lakshmi CNP, Atmika P, Anbarasu K, Mahalingam S. Global Quantitative Proteomics reveal Deregulation of Cytoskeletal and Apoptotic Signalling Proteins in Oral Tongue Squamous Cell Carcinoma. Nature Scientific Reports 2018; 8 (1):1567.
- Krishnan R, Boddapati N, Mahalingam S. Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation. Nature Scientific Reports 2018; 8(1):11421.
- Karthik IP, Desai P, Sukumar S, Dimitrijevic A, Rajalingam K, Mahalingam S. E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases. Journal of Biological Chemistry 2018; 293 (15): 5624-5635.
- Kumaraswamy A, Mamidi A, Desai P, Sivagnanam A, Perumalsamy LR, Ramakrishnan C, Gromiha M, Rajalingam K, Mahalingam S. (2018) The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function. Journal of Biological Chemistry. 293(40):15691-15705.
- Datta D., Anbarasu K., Rajabather S., Priya R.S., Desai P., Mahalingam S. Nucleolar GTP-binding protein-1 (NGP-1) promotes G1 to S phase transition by activating cyclin-dependent kinase inhibitor p21Cip1/Waf1 2015 Journal of Biological Chemistry 290 (35): 21536-21552.
- Thoompumkal I.J., Rehna K., Anbarasu K., Mahalingam S. Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation 2016 Cell Cycle 15 (23): 3251-3267.
- Suryaraja R., Anitha M., Anbarasu K., Kumari G., Mahalingam S. The E3 ubiquitin ligase itch regulates tumor suppressor protein RASSF5/NORE1 stability in an acetylation-dependent manner 2013 Cell Death and Disease (4): 3.
- NeelimaBoddapati, Anbarasu K, Suryaraja R, Ashish V. Tendulkarand Mahalingam.S. Sub-cellular distribution of Human Putative NucleolarGTPase, GNL1 is regulated by a Novel Arginine-lysine-rich and GTP-binding domains in a Cell Cycle Dependent Manner. Journal of Molecular Biology 416: 346-366.
- Pankaj Gupta, P. K. Singhal, P. Rajendrakumar, Y. Padwad, A. V. Tendulkar, V.S. Kalyanaraman, R. E. Schmidt, A. Srinivasan, and Mahalingam S. (2011). Mechanism of host cell MAPK/ERK-2 Incorporation into Lentivirus Particles: Characterization of the Interaction between MAPK/ERK-2 and Proline-rich Domain Containing Capsid Region of Structural Protein Gag. Journal of Molecular Biology 410(4):681-697.
- Chennupati V, Datta D, Malireddi RS, Boddapati N, Kayasani M, Sankaranarayanan R, Mishra M, Seth P, Mani C, and Mahalingam S. Signals and Pathways Regulating Nucleolar Retention of Novel Putative NucleolarGTPase, NGP-1(GNL-2). Biochemistry50(21):4521-36.
- Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional Interaction of the Ras Effector RASSF5 with the Tyrosine Kinase Lck: Critical Role in Nucleocytoplasmic Transport and Cell Cycle Regulation.Journal of Molecular Biology397(1):89-109.
- Kumari G and MahalingamS. (2009). Extracellular signal-regulated kinase 2 (ERK-2) mediated phosphorylation regulates nucleo-cytoplasmic shuttling and cell growth control of Ras-associated tumor suppressor protein, RASSF2.Exp Cell Res. 315(16):2775-2790
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- Srinivasan A, Ayyavoo V, Mahalingam S, Kannan A, Boyd A, Datta D, Kalyanaraman VS, Cristillo A, Collman RG, Morellet N, Sawaya BE, Murali R. (2008). A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr: potential impact on CTL epitopes..Virol J. 5: 99-115.
- Kumari, P. K. Singhal, M.R.K., Subba Rao, and Mahalingam S. (2007). Nuclear Transport of Ras Associated Tumor Suppressor Proteins: Different Receptor Binding Specificities for Arginine-rich Nuclear Targeting Signals. Journal of Molecular Biology. 367: 1294-1311.
- Rao, M.R.K., Gita Kumari., D. Balasundaram., R. Sankaranarayanan and Mahalingam S. (2006). A Novel Lysine-rich domain and GTP Binding Motifs Regulates the Nucleolar Retention of Human Guanine Nucleotide Binding Protein, GNL3L. Journal of Molecular Biology. 364: 637-654.
- Singhal, P.K., Rajendra Kumar. P., Subba Rao. M.R.K., Kyasani. M., and Mahalingam S. (2006). Simian Immunodeficiency Virus Vpx is imported into the nucleus via importin alpha dependent and independent pathways. Journal of Virology. 80: 526-536.
- Du X., Subba Rao M.R.K., Chen X.Q., Wu W., Mahalingam S., The homologous putative GTPases Grn1p from fission yeast and the human GNL3L are required for growth and play a role in processing of nucleolar pre-rRNA 2006 Molecular Biology of the Cell 17 (1): 460-474.
- Varadarajan P, Mahalingam S, Liu P, Ng SB, Gandotra S, Dorairajoo DS, Balasundaram D. (2005). The functionally conserved nucleoporins Nup124p from fission yeast and the human Nup153 mediate nuclear import and activity of the Tf1 retrotransposon and HIV-1 Vpr. Mol. Biol. Cell 16: 1823-1838. 27, 160, 2006.
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