Research in the Krishnamurthy lab focuses on host response during viral infections. Our studies address the fundamental mechanisms by which cells resist infection and how cells know they are infected by a virus. The innate immune pathway is the first line of defense against viruses and functions to limit viral replication and spread. Pattern-Recognition Receptors including Rig-I-like helicases (Rig-I and MDA5) and Toll-like receptors (TLRs) recognize conserved microbial features (Pathogen associated Molecular Pattern, PAMP) and provide signals to initiate immune response by producing type I IFN and cytokines. Double stranded RNA produced during viral infections serves as PAMP and activates the IFN-inducible 2’,5’ - oligoadenylate synthetase (OAS) which converts cellular ATP to unique 2’,5’ - linked oligoadenylates, 2-5A, which binds and activates a ubiquitous and latent endoribonuclease, RNase L. Activated RNase L cleaves single stranded viral and host RNAs to produce small RNAs with duplex structures which can signal through Rig-I and MDA5 to amplify the production of IFN-β. Studies in the lab are aimed at investigating the signaling pathway initiated by small RNA cleavage products of RNase L and the expanding roles of RNase L in innate immunity.
Areas of research in our group include:
1. Regulation of autophagy and cell death pathways
2. Non-enzymatic antiviral role of RNase L
3. Role of small cellular RNAs generated by RNaseL in innate immunity
4. RNase L-Filamin A interaction in prostate cancer
Adnan Ali Rammouni
Kirsten Neytania Clark
Omaima Farid Ahmad
Current Laboratory Grants
National Institutes of Health, NIAID, R15 (02/2016- 01/2019), Novel role of RNA signaling in cross-talk between autophagy and apoptosis.
(** Graduate student, # Undergraduate student)
The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate
Ezelle HJ, Malathi K, Hassel BA. Int J Mol Sci. 2016 Jan 8;17(1). pii: E74. doi: 10.3390/ijms17010074. PMID: 26760998.
“Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy” Klionsky, D et al., Autophagy. 2016 Jan 2;12(1):1-222. PMID: 26799652
RNase L cleavage products promote switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1. Siddiqui, MA**, Mukherhee, S, Manivannan, P** and Malathi K* Int. J. Mol. Sci. 2015, 16, 17611-17636; doi:10.3390/ijms160817611. *Communicating author).
RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry. Malathi K*, Siddiqui MA**, Dayal S**, Naji M#, Ezelle HJ, Zeng C, Zhou A, Hassel BA. MBio. 2014 Oct 28;5(6):e02012. doi: 10.1128/mBio.02012-14.PMID:25352621(*Communicating author).
RNase L contributes to experimentally induced type 1 diabetes onset in mice. Zeng C, Yi X, Zipris D, Liu H, Zhang L, Zheng Q, Malathi K, Jin G, Zhou A. J Endocrinol. 2014 Dec;223(3):277-87. doi: 10.1530/JOE-14-0509. Epub 2014 Oct 6. PMID:25287058.
Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells. Mukherjee S, Siddiqui MA**, Dayal S**, Ayoub YZ# and Malathi K*. J Inflamm Res. Jun 17;7:89-101, 2014 (*Communicating author).
Siddiqui MA**, Malathi K*. RNase L induces autophagy via c-Jun N-terminal kinase and double-stranded RNA-dependent protein kinase signaling pathways. J Biol Chem. 2012 Dec 21;287(52):43651-64. (*Communicating author).
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.
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.