Dr Srikanth’s research focuses on understanding the mechanisms involved in regulating the cellular nucleic acid sensing pathways. Our lab recently identified an important role of Stromal interaction molecule 1 (STIM1), a component of the store-operated Ca2+ entry (SOCE) channels, in maintaining the resting state of stimulator of interferon genes (STING), an endoplasmic reticulum-resident cellular DNA sensor and adaptor protein, under sterile conditions. Since most DNA sensors do not differentiate between pathogen or host DNA, aberrant activation of STING due to genomic or mitochondrial DNA in the cytoplasm has been implicated in various autoinflammatory diseases. Conversely, due to its essential role in stimulating the adaptive immune response, STING agonists, in conjunction with checkpoint blockade, are being actively tested for cancer immunotherapy. Hence a thorough understanding of the mechanisms involved in positive or negative regulation of this pathway is critical for the treatment of autoinflammatory disorders or cancers. We are also examining the role of the pore component of the SOCE channels, Orai proteins in regulation of T cell functions.
Feske S*, Gwack Y*, Prakriya M, Srikanth S, Puppel S, Tanasa B, Hogan PG, Lewis RS, Daly M and Rao A. A mutation in Orai1 causes immune deficiency by abrogating store-operated Ca2+ entry and CRAC channel function. Nature. 2006, 441(7090), 179-185. PMID: 16582901. (* co-first authors)
Kim KD*, Srikanth S*, Tan VY, Yee MK, Jew M, Damoiseaux R, Jung ME, Shimizu S, An DS, Ribalet B, Waschek JA, Gwack Y. Calcium Signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. Journal of Immunology, 2014, Jan 1;192(1):110-22. PMID: 24307733. PMCID: PMC3874217. (* co-first authors).
Srikanth S*,#, Kim KD*, Gao Y, Woo JS, Ghosh S, Paz A, Abramson J, Jiang M, and Gwack Y#. A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals. Science Signaling, 2016 Mar 22; 9(420): ra31. PMID 27016526. PMCID: PMC5013727. (*co-first authors, #Corresponding authors).
Srikanth S*, #, Woo JS*, Wu B, El-Sherbiny YM, Leung J, Chupradit K, Rice L, Seo GJ, Calmettes G, Ramakrishna C, Cantin E, An DS, Sun R, Wu TT, Jung JU, Savic S, Gwack Y#. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat Immunol. 2019 Feb20; 2:152-162. PMID: 30643259. PMCID: PMC6340781. (* equal contribution, # senior authors).
Rice L, Stockdale C, Berry I, O'Riordan S, Pysden K, Anwar R, Rushambuza R, Blyth M, Srikanth S, Gwack Y, El-Sherbiny YM, Carter C, Savic S. A Report of Novel STIM1 Deficiency and 6-Year Follow-Up of Two Previous Cases Associated with Mild Immunological Phenotype. J Clin Immunol. 2019 Apr;39: 249-56. PMID: 30949876.