S Mahalingam

S Mahalingam

Ph.D., Madurai Kamaraj University
M.Sc., Madurai Kamaraj University
Office: Block:2 BT 105
Tel: +91-44-2257-5116
Email: mahalingam@iitm·ac·in
Lab: BT 101 (Website)

Research Interests

  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.

  1. Tumor Biology

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.

  1. Career Profile
  • Associate Professor, Department of Biotechnology, Indian Institute of Technology Madras, Chennai(May 2007- present).
  • 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).

Selected Publications

  1. Suryaraja R, Anitha M, Anbarasu K, Kumari G, Mahalingam S. (2013). The E3 ubiquitin ligase Itch regulates tumor suppressor protein RASSF5/NORE1 stability in an acetylation-dependent manner. Cell Death Dis. 4:e565-574.
  2. Boddapati N, Anbarasu K, Suryaraja R, Tendulkar AV, Mahalingam S. (2012). Subcellular distribution of the human putative nucleolar GTPase GNL1 is regulated by a novel arginine/lysine-rich domain and a GTP binding domain in a cell cycle-dependent manner. Journal of Molecular Biology 416(3):346-66.
  3. 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.
  4. Chennupati V, Datta D, Malireddi RS, Boddapati N, Kayasani M, Sankaranarayanan R, Mishra M, Seth P, Mani C, and Mahalingam S. (2011). Signals and Pathways Regulating Nucleolar Retention of Novel Putative Nucleolar GTPase, NGP-1(GNL-2). Biochemistry 50(21):4521-4536.
  5. Kumari G, Singhal PK, Suryaraja R, Mahalingam S 2010. Functional Interaction of the Ras Effector RASSF5 with the Tyrosine Kinase Lck: Critical Role in Nucleocytoplasmic Transport and Cell Cycle Regulation. Journal of Molecular Biology 397(1):89-109.
  6. Kumari G and Mahalingam S. (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.
  7. Pandey. R.C. Datta. D. Mukerjee,. R. Srinivasan. A Mahalingam. S* and B. E. Sawaya*. (2009). HIV-1 Vpr: a closer look at the multifunctional protein from the structural perspective. Current HIV Research .7(2): 114-128. (*both are corresponding authors).
  8. 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.
  9. Gita Kumari, P. K. Singhal, M.R.K., Subba Rao, and S. Mahalingam. (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.
  11. Subba Rao, M.R.K., Gita Kumari., D. Balasundaram., R. Sankaranarayanan and S. Mahalingam. (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.
  12. Singhal,P. K., P. Rajendra Kumar., M. R. K. Subba Rao and S. Mahalingam (2006). Nuclear Export of Simian Immunodeficiency Virus Vpx Protein. Journal of Virology. 80: 12271-12282.
  13. 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.
  14. Du.X., Subba Rao. M.R.K., Chen, X.Q., Wei. W., Mahalingam. S, and Balasundaram. D. (2006). 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. Mol. Biol. Cell. 1: 460-474. 27, 1355, 2006.
  15. Varadarajan. P., Mahalingam. S., Gandotra,S, Dorairajoo. D.S., D�souza VM, Balasundarum 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.
  16. Rajendra Kumar, P., Singhal, P.K, Subba Rao. M.R.K., and Mahalingam. S. (2005). Phosphorylation by MAPK regulates simian immunodeficiency virus Vpx protein nuclear import and virus infectivity. J. Biol. Chem. 280: 8553-8563. 32, 6335, 2005.
  17. Rajendra Kumar, P., Singhal, P.K, Vinod, S.S and Mahalingam. S. (2003). A non-canonical transferable signal mediates nuclear import of simian immunodeficiency virus Vpx protein. Journal of Molecular Biology 331: 1141-1156. 6, 2040, 2005.
  18. Mahalingam. S., Van Tine. B., Santiago. M.L., Gao. F., Shaw. G.M., and Hahn. B. (2001). Functional analysis of the Simian Immunodeficiency virus Vpx protein: Identification of packaging determinants and a novel nuclear targeting domain. Journal of Virology. 75: 362-374. 54, 1304, 2005.
  19. Mahalingam. S., Ayyavoo. V., Patel. M., Kiebber-Emmons. T., Kao. G.D., Muschel. R.J, and Weiner. D.B. (1998). HIV-1 Vpr interacts with a human 34-mov34 homologue, a cellular factor linked to the G2/M phase transition of the mammalian cell cycle. Proc. Natl. Acad. Sci. USA 95: 3419-3424. 26, 3941, 2005.
  20. Ayyavoo. V., Mahboubi. A., Mahalingam. S., Ramalingam. R., Williams. W.V., Sagar. K., Green. D, and Weiner. D.B. (1997). HIV-1 Vpr suppresses immune activation and apoptosis through regulation of NF-kB. Nature Medicine 3: 1117-1123. 26, 3495, 2005.
  21. Mahalingam. S., Ayyavoo. V., Patel. M., Kieber-Emmons. T, and Weiner. D.B. (1997). Nuclear import, Virion incorporation and Cell cycle arrest/differentiation are mediated by distinct functional domains of HIV-1 Vpr. Journal of Virology. 71: 6339-6347. 5, 1489, 2004.
  22. Kim. J.J., Bagarazzi. M.L., Trivedi. N., Hu. Y., Kazahaya. K., Wilson. D.M., Chattergoon. M.A., Dang. K., Mahalingam. S., Chalian. A.A., Agadjanyan. M.G., Boyer. J.D., Wang. B, and Weiner. D.B. (1997). Engineering of in vivo immune reponses to DNA immunization via codelivery of costimulatory molecule genes. Nature Biotechnology. 15: 641-646. 24, 2205, 2003.
  23. Mahalingam. S., Collman. R.G., Patel. M., Monken. C.E, and Srinivasan. A. (1995). Functional analysis of HIV-1 Vpr: Identification of determinants essential for subcellular localization. Virology 212: 331-339. 65, 204, 2003.
  24. Mahalingam. S., Khan. S.A., Murali. R., Jabbar. M.A., Monken. C.E., Collman. R.G, and Srinivasan. A. (1995). Mutagenesis of the putative α-helical domain of the Vpr protein of HIV- 1: Effect on stability and virion incorporation. Proc. Natl. Acad. Sci. USA 92: 3794-3798.

Book Chapter

  1. Rajendra Kumar. P., Singhal. P.K, and Mahalingam. S. (2004) A transferable signal mediates nuclear import of simian immunodeficiency virus Vpx protein. 173-178. Deep Roots, Open Skies: New Biology in India. Eds. S.K. Basu., Batra J.K and D.M. Salunke. Narosa Publishing House, New Delhi, India.
  2. Srilakshmi, P., Rajendra Kumar. P and Mahalingam. S. (2007) HIV-1 pathogenesis: Role of viral protein R. 186-200. Research Issues in HIV/AIDS. Eds. D. Raghunath and C. Durga Rao.Tat McGraw-Hill Publishing company Limited, New Delhi.