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Biological Sciences Department Faculty
Host response against viruses involves both innate and adaptive immune mechanisms. Viral persistence caused by impaired host defense responses is a common cause of inflammation. Several studies indicate that presence of pathogens can be a stimulatory factor in the tumor developing effect of inflammation. My long term goal is to understand the regulation of host signaling mechanism in antiviral response and how chronic inflammation arising from dysregulation of innate immune processes can promote tumorigenesis. Viruses are recognized in the cells by the nucleic acid-recognizing Toll-like receptors (TLRs) or the cytosolic Rig-like receptors (RLRs). Early response to viruses include production of type I interferon (IFN) which in turn induces transcription of IFN-stimulated genes (ISGs) and enzymes which impede viral replication and production of cytokines which promote an adaptive immune response. The focus of research in my lab is:
1. To study the pro-inflammatory pathways activated by the viral clearance mechanism and how its aberrant regulation can act to allow persistent inflammation. One of the approaches would involve dissecting the pathway involved in production of interferon from the pro-inflammatory pathway that is involved in production of cytokines and chemokines. This effort can help us to better understand the role of inflammation in initiating tumor behavior and progression which in turn will further the development of approaches designed to block critical early events during neoplastic progression.
2. During viral infection, double stranded RNA (dsRNA) produced as replicative intermediates or viral dsRNA genome activates the IFN-inducible 2’,5’ - oligoadenylate synthetase (OAS) which converts cellular ATP to unique 2’,5’ - linked oligoadenylates, 2-5A. The trimeric and tetrameric oligomers of 2-5A activate a ubiquitous and latent endoribonuclease, RNase L, which cleaves viral and cellular single-stranded regions of RNA on 3’ end of UpAp and UpUp releasing small RNAs with duplex structures. Another area of research is to investigate the signaling pathway initiated by small RNA cleavage products of RNase L in innate immunity. Understanding the role of small RNAs generated by RNase L in host response can provide new strategies to suppress viral infection and inflammation.
3. To determine the contribution of miRNAs in host clearance mechanisms of viral infections.
M. A. Siddiqui and K. Malathi. RNase L Induces Autophagy via c-Jun N-terminal Kinase and Double-stranded RNA-dependent Protein Kinase Signaling Pathways. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 52, pp. 43651–43664, December 21, 2012.
Malathi K, Saito T, Crochet N, Barton DJ, Gale M Jr, Silverman RH. RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP. RNA. Nov;16(11):2108-19, 2010.
Malathi K, Dong B, Gale M and Silverman RH. Small self RNA generated by RNase L amplifies Antiviral Innate Immunity. Nature. Aug 16;448(7155):816-9, 2007.
Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA, Ganem D, Derisi JL, Chow SA, Silverman RH. From the Cover: An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proc Natl Acad Sci U S A. Jan 30;104(5):1655-60, 2007.
Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH. Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. Nucleic Acids Res. 34(22):6684-95, 2006.
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. Mar;2(3):e25, 2006.
Malathi, K., Paranjape, J.M., Bulanova, E., Shim, M., Guenther-Johnson, J.M., Faber, P.W., Eling, T.E., Williams, B.R.G., and Silverman, R.H. A novel transcriptional signaling pathway in the interferon system mediated by 2'-5'-oligoadenylate activation of RNase L. Proc. Natl. Acad. Sci. U.S.A., 102, 14533-14538, 2005.
Zhou, A., Molinaro, R.J., Malathi, K., and Silverman, R.H. Mapping of the human RNASEL promoter and expression in cancer and normal cells. J. Interferon & Cyt. Res., 25, 595-603, 2005.
Malathi K., Li X, Krizanova O, Ondrias K, Sperber K, Ablamunits V, Jayaraman T. Cdc2/cyclin B1 interacts with and modulates inositol 1,4,5-trisphosphate receptor (type 1) functions. J Immunol. 2005 Nov 1;175(9):6205-10.
Malathi K, Paranjape JM, Ganapathi R, Silverman RH. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2004 Dec 15;64(24):9144-51.
Tantral, L., Malathi, K., Kohyama, S., Silane, M., Berenstein, A., and Jayaraman, T. Intracellular calcium release is required for caspase-3 and –9 activation. Cell Biochem. and Function. 22(1): 35-40. 2004.
Malathi, K., Higaki, K., Tinkelenberg, A.H., Balderes, D.A., Almanzar, D., Wilcox, L., Erdeniz, N., Redican, F., Padamsee, M, Liu, Y., Khan, S., Alcantara, F., Carstea, E.D., Morris, J.A., and Sturley, S.L. Mutagenesis of the putative sterol sensing domain of the yeast Niemann Pick C related protein reveals a primordial role in subcellular sphingolipid distribution. J Cell Biol.164(4):547-56. 2004
Editorial on the above paper ` A primordial mover of sphingolipids’ in J. Cell Biol. 164(4): 476, 2004.
Malathi, K., Kohyama, S., Ho, M., Soghoian, D., Li, X., Silane, M., Berenstein, A., and Jayaraman, T. Inositol 1,4,5-triphosphate receptor (type 1) phosphorylation and modulation by cdc2. J. Cell. Biochem.90(6): 1186-96, 2003.
Malathi,K., Xiao, Y., and Mitchell, A.P. Catalytic roles of yeast GSK3beta/shaggy homolog Rim11p in meiotic activation. Genetics. 153:1145-1152. 1999.
Malathi,K., Xiao, Y., and Mitchell.A.P. Interaction of yeast repressor-activator protein Ume6p with glycogen synthase kinase 3 homolg Rim11p. Mol. Cell. Biol. 17(12): 7230-7236. 1997.
Malathi, K., Ganesan , K.,and Datta, A. Identification of a putative transcription factor in C.albicans that can complement the mating defect of S.cerevisiae ste12 mutants. J. Biol. Chem. 269: 22945-51. 1994.
Singh,P., Ganesan, K. , Malathi,K., Ghosh, D., and Datta, A. ACPR, a STE12 homologue from C.albicans, is a strong inducer of pseudohyphae in S.cerevisiae haploids and diploids. Biochem. Biophys. Res. Comm. 205 (2) 1079-85. 1994.
Mohammad Adnan Siddiqui