Chinnaswamy Tiruppathi

A major interest in my laboratory is focused on Ca2+ signaling pathways regulating inflammation. I study Ca2+ entry through TRPC channels as an indispensable causal link in the pathogenesis of inflammation. Studies are also identifying STIM1-activated Ca2+ entry through TRPC channels that mediates STIM1 phosphorylation that serves as an “off switch” for Ca2+ entry in endothelial cells.

Another major interest of my laboratory is on defining the roles of NF-κB signaling pathways activated downstream of TLR4 in mediating and resolving vascular inflammation. The deubiquitinase A20 is vital for the maintenance of immune homeostasis. A20 attenuates the inflammatory responses by suppressing unchecked TAK1-mediated NF-κBand p38 MAPK activation. However, the transcriptional mechanism of A20 expression is poorly understood. We made a seminal discovery in that we showed that the transcription repressor DREAM (KCNIP3) bound to the promoter of the gene encoding A20 (TNFAIP3) to repress expression of this deubiquitinase, which suppresses inflammatory NF-κB signaling (Nat Immunol, 15:209-247, 2014). DREAM (KCNIP3)-deficient (KCNIP3−/−) mice displayed unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE-associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases with uncontrolled NF-κB signaling activity, such as acute lung injury. We are focusing on the role of TAK1-dependent NF-κB and p38 MAPK activation in signaling inflammatory lung injury through induction of STIM1, ICAM-1, and DREAM.

Tiruppathi C, Soni D, Wang DM, Xue J, Singh V, Thippegowda PB, Cheppudira BP, Mishra RK, DebRoy A, Qian Z, Bachmaier K, Zhao Y, Christman JW, Vogel SM, Ma A, Malik AB. The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nat Immunol. 15:239-247, 2014.

Sundivakkam PC, Natarajan V, Malik AB, Tiruppathi C. Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 mediates STIM1 Phosphorylation to inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase. J Biol Chem. 288:17030-17041, 2013.

Sundivakkam PC, Freichel M, Singh V, Yuan JP, Vogel SM, Flockerzi V, Malik AB, Tiruppathi C. Ca2+ Sensor STIM1 is Necessary and Sufficient for the Store-Operated Ca2+ Entry Function of Transient Receptor Potential Canonical (TRPC) 1 and 4 Channels in Endothelial Cells. Mol Pharmacol. 81:510-526, 2012.

Thippegowda PB, Singh V, Sundivakkam PC, Xue J, Malik AB, Tiruppathi C. Ca2+ influx via TRPC channels induces NF-κB-dependent A20 expression to prevent thrombin-induced apoptosis in endothelial cells. Am J Physiol Cell Physiol.298:C656-C664, 2010.

Bair AM, Thippegowda PB,Freichel M, Cheng N, Ye RD, Vogel SM, Yu Y, Flockerzi V, Malik AB, Tiruppathi C. Ca2+ Entry via TRPC Channels is Necessary for Thrombin-Induced NF-κB Activation in Endothelial Cells Through AMP-Activated Protein Kinase and Protein Kinase Cδ. J Biol Chem. 284:563-574, 2009.

Tiruppathi C, Shimizu J, Miyawaki-Shimizu K, Vogel SM, Bair AM, Minshall RD, Predescu D, Malik AB. Role of NF-κB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by LPS. J Biol Chem.283:4210-4218, 2008.

Bachmaier k, Toya S, Garrean S, Triantafillou T, Frey R, Gao X, Vogel SM, Minshall RD, Christman JW, Tiruppathi C,Malik AB. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med. 13:920-926, 2007.

Jho D, Mehta D, Ahmmed G, Gao XP, Tiruppathi C, Broman M, Malik AB. Angiopoietin-1 opposes VEGF-induced increase in endothelial permeability by inhibiting TRPC1-dependent Ca2 influx. Circ Res. 96:1282-90, 2005.