Affiliations

Associate Professor, Physiology

Member, CTSI, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, JCCC Signal Transduction and Therapeutics Program Area, Molecular, Cellular & Integrative Physiology GPB Home Area

Ca2+ signaling pathways are universally present and regulate processes ranging form cell differentiation to cell death. In many different cell types including the cells of the immune system, the depletion of intracellular endoplasmic reticulum Ca2+ stores by the receptor stimulation triggers Ca2+ entry through plasma membrane store-operated Ca2+ channels known as Ca2+ release-activated Ca2+ (CRAC) channels. The process of store-operated Ca2+ influx is critical for the immune responses in T cells as revealed by the pharmacological or knock-out mice studies targeting the well known downstream components of Ca2+ signaling pathway like NFAT (Nuclear Factor of Activated T cells) family of Ca2+-regulated transcription factors or calcineurin. Although the CRAC current was defined electrophysiologically in the early 80s���, the molecular identity of the CRAC channel stayed elusive till last year when we and other groups discovered the gene encoding a critical subunit of the CRAC channels. The gene was name by Dr. Gwack as Drosophila Orai (dOrai) and its mammalian homologues as Orai1, -2, -3. Dr. Gwack and colleagues used dual approach of genome-wide RNAi screen in Drosophila cells and a positional cloning method from human severe combined immune deficiency (SCID) patient cells to nail down Orai1 as the pore component of the CRAC channel. The importance of the CRAC channels was evident from the human SCID patients harboring single missense mutation in the coding sequence of Orai1 that abrogated store-operated Ca2+ influx in the T cells and fibroblasts of these patients. The identification of Orai for the first time gives us a molecular handle to study the macromolecular structure and mechanism of regulation of the CRAC channels. The long term objective of our research involves identification of the other components of the CRAC channel complex and development of possible therapeutic agents targeting the CRAC channels.

Srikanth Sonal, Gwack Yousang Measurement of intracellular Ca2+ concentration in single cells using ratiometric calcium dyes. Methods in molecular biology (Clifton, N.J.). 2013; 963(3): 3-14. Srikanth Sonal, Gwack Yousang Orai1-NFAT signalling pathway triggered by T cell receptor stimulation. Molecules and cells. 2013; 35(3): 182-94. Srikanth Sonal, Ribalet Bernard, Gwack Yousang Regulation of CRAC channels by protein interactions and post-translational modification. Channels (Austin, Tex.). 2013; 7(3): . Srikanth Sonal, Jew Marcus, Kim Kyun-Do, Yee Ma-Khin, Abramson Jeff, Gwack Yousang Junctate is a Ca2+-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(22): 8682-7. Srikanth Sonal, Gwack Yousang Orai1, STIM1, and their associating partners. The Journal of physiology. 2012; 590(Pt 17): 4169-77. Kim Kyun-Do, Srikanth Sonal, Yee Ma-Khin Win, Mock Dennis C, Lawson Gregory W, Gwack Yousang ORAI1 deficiency impairs activated T cell death and enhances T cell survival. Journal of immunology (Baltimore, Md. : 1950). 2011; 187(7): 3620-30. Newton Ryan H, Leverrier Sabrina, Srikanth Sonal, Gwack Yousang, Cahalan Michael D, Walsh Craig M Protein kinase D orchestrates the activation of DRAK2 in response to TCR-induced Ca2+ influx and mitochondrial reactive oxygen generation. Journal of immunology (Baltimore, Md. : 1950). 2011; 186(2): 940-50. Srikanth Sonal, Yee Ma-Khin Win, Gwack Yousang, Ribalet Bernard The third transmembrane segment of orai1 protein modulates Ca2+ release-activated Ca2+ (CRAC) channel gating and permeation properties. The Journal of biological chemistry. 2011; 286(40): 35318-28. Srikanth Sonal, Jung Hea-Jin, Kim Kyun-Do, Souda Puneet, Whitelegge Julian, Gwack Yousang A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells. Nature cell biology. 2010; 12(5): 436-46. Srikanth Sonal, Jung Hea-Jin, Ribalet Bernard, Gwack Yousang The intracellular loop of Orai1 plays a central role in fast inactivation of Ca2+ release-activated Ca2+ channels. The Journal of biological chemistry. 2010; 285(7): 5066-75. E Xiaofei, Hwang Seungmin, Oh Soohwan, Lee Jong-Soo, Jeong Joseph H, Gwack Yousang, Kowalik Timothy F, Sun Ren, Jung Jae U, Liang Chengyu Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLoS pathogens. 2009; 5(10): e1000609. Barr Valarie A, Bernot Kelsie M, Srikanth Sonal, Gwack Yousang, Balagopalan Lakshmi, Regan Carole K, Helman Daniel J, Sommers Connie L, Oh-Hora Masatsugu, Rao Anjana, Samelson Lawrence E Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Molecular biology of the cell. 2008; 19(7): 2802-17. Gwack Yousang, Srikanth Sonal, Oh-Hora Masatsugu, Hogan Patrick G, Lamperti Edward D, Yamashita Megumi, Gelinas Curtis, Neems Daniel S, Sasaki Yoshiteru, Feske Stefan, Prakriya Murali, Rajewsky Klaus, Rao Anjana Hair loss and defective T- and B-cell function in mice lacking ORAI1. Molecular and cellular biology. 2008; 28(17): 5209-22. Gwack Yousang, Srikanth Sonal, Feske Stefan, Cruz-Guilloty Fernando, Oh-hora Masatsugu, Neems Daniel S, Hogan Patrick G, Rao Anjana Biochemical and functional characterization of Orai proteins. The Journal of biological chemistry. 2007; 282(22): 16232-43. Ong Hwei Ling, Cheng Kwong Tai, Liu Xibao, Bandyopadhyay Bidhan C, Paria Biman C, Soboloff Jonathan, Pani Biswaranjan, Gwack Yousang, Srikanth Sonal, Singh Brij B, Gill Donald L, Gill Donald, Ambudkar Indu S Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. The Journal of biological chemistry. 2007; 282(12): 9105-16. Gwack Yousang, Feske Stefan, Srikanth Sonal, Hogan Patrick G, Rao Anjana Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell calcium. 2007; 42(2): 145-56. Gwack Yousang, Sharma Sonia, Nardone Julie, Tanasa Bogdan, Iuga Alina, Srikanth Sonal, Okamura Heidi, Bolton Diana, Feske Stefan, Hogan Patrick G, Rao Anjana A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature. 2006; 441(7093): 646-50. Feske Stefan, Gwack Yousang, Prakriya Murali, Srikanth Sonal, Puppel Sven-Holger, Tanasa Bogdan, Hogan Patrick G, Lewis Richard S, Daly Mark, Rao Anjana A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006; 441(7090): 179-85. Prakriya Murali, Feske Stefan, Gwack Yousang, Srikanth Sonal, Rao Anjana, Hogan Patrick G Orai1 is an essential pore subunit of the CRAC channel. Nature. 2006; 443(7108): 230-3. Chang Heesoon, Gwack Yousang, Kingston Dior, Souvlis John, Liang Xiaozhen, Means Robert E, Cesarman Ethel, Hutt-Fletcher Lindsey, Jung Jae U Activation of CD21 and CD23 gene expression by Kaposi's sarcoma-associated herpesvirus RTA. Journal of virology. 2005; 79(8): 4651-63. Lee Sun-Hwa, Chung Young-Hwa, Cho Nam-Hyuk, Gwack Yousang, Feng Pinghui, Jung Jae U Modulation of T-cell receptor signal transduction by herpesvirus signaling adaptor protein. Molecular and cellular biology. 2004; 24(12): 5369-82. Nakamura Hiroyuki, Lu Michael, Gwack Yousang, Souvlis John, Zeichner Steven L, Jung Jae U Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator. Journal of virology. 2003; 77(7): 4205-20. Hwang Seungmin, Lee Daeyoup, Gwack Yousang, Min Hyesun, Choe Joonho Kaposi's sarcoma-associated herpesvirus K8 protein interacts with hSNF5. The Journal of general virology. 2003; 84(Pt 3): 665-76. Gwack Yousang, Nakamura Hiroyuki, Lee Sun Hwa, Souvlis John, Yustein Jason T, Gygi Steve, Kung Hsing-Jien, Jung Jae U Poly(ADP-ribose) polymerase 1 and Ste20-like kinase hKFC act as transcriptional repressors for gamma-2 herpesvirus lytic replication. Molecular and cellular biology. 2003; 23(22): 8282-94. Gwack Yousang, Baek Hwa Jin, Nakamura Hiroyuki, Lee Sun Hwa, Meisterernst Michael, Roeder Robert G, Jung Jae U Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi's sarcoma-associated herpesvirus RTA-mediated lytic reactivation. Molecular and cellular biology. 2003; 23(6): 2055-67. Lim Chunghun, Sohn Hekwang, Lee Daeyoup, Gwack Yousang, Choe Joonho Functional dissection of latency-associated nuclear antigen 1 of Kaposi's sarcoma-associated herpesvirus involved in latent DNA replication and transcription of terminal repeats of the viral genome. Journal of virology. 2002; 76(20): 10320-31. Gwack Yousang, Hwang Seungmin, Lim Chunghun, Won Young Suk, Lee Chul Ho, Choe Joonho Kaposi's Sarcoma-associated herpesvirus open reading frame 50 stimulates the transcriptional activity of STAT3. The Journal of biological chemistry. 2002; 277(8): 6438-42. Byun Hyewon, Gwack Yousang, Hwang Seungmin, Choe Joonho Kaposi's sarcoma-associated herpesvirus open reading frame (ORF) 50 transactivates K8 and ORF57 promoters via heterogeneous response elements. Molecules and cells. 2002; 14(2): 185-91. He Zhiheng, Wang Fei, Ma Jian, Sen Subha, Zhang Jing, Gwack Yousang, Zhou Yu, Sun Zuoming Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment. Journal of immunology (Baltimore, Md. : 1950). 2016; . Lee Sung Hee, Rigas Nicole Kristina, Lee Chang-Ryul, Bang April, Srikanth Sonal, Gwack Yousang, Kang Mo K, Kim Reuben H, Park No-Hee, Shin Ki-Hyuk Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma. Oncotarget. 2016; . Srikanth Sonal, Woo Jin Seok, Gwack Yousang A large Rab GTPase family in a small GTPase world. Small GTPases. 2016; 1-6. Lee Sung Hee, Park Yongtae, Song Minju, Srikanth Sonal, Kim Sol, Kang Mo K, Gwack Yousang, Park No-Hee, Kim Reuben H, Shin Ki-Hyuk Orai1 mediates osteogenic differentiation via BMP signaling pathway in bone marrow mesenchymal stem cells. Biochemical and biophysical research communications. 2016; 473(4): 1309-14. Srikanth Sonal, Kim Kyun-Do, Gao Yuanyuan, Woo Jin Seok, Ghosh Shubhamoy, Calmettes Guillaume, Paz Aviv, Abramson Jeff, Jiang Meisheng, Gwack Yousang A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals. Science signaling. 2016; 9(420): ra31. Woo Jin Seok, Srikanth Sonal, Nishi Miyuki, Ping Peipei, Takeshima Hiroshi, Gwack Yousang Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca2+ dynamics in T cells. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(10): 2762-7. Nurbaeva Meerim K, Eckstein Miriam, Concepcion Axel R, Smith Charles E, Srikanth Sonal, Paine Michael L, Gwack Yousang, Hubbard Michael J, Feske Stefan, Lacruz Rodrigo S Dental enamel cells express functional SOCE channels. Scientific reports. 2015; 5(10): 15803. Bertin Samuel, Aoki-Nonaka Yukari, de Jong Petrus Rudolf, Nohara Lilian L, Xu Hongjian, Stanwood Shawna R, Srikanth Sonal, Lee Jihyung, To Keith, Abramson Lior, Yu Timothy, Han Tiffany, Touma Ranim, Li Xiangli, González-Navajas José M, Herdman Scott, Corr Maripat, Fu Guo, Dong Hui, Gwack Yousang, Franco Alessandra, Jefferies Wilfred A, Raz Eyal The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4⁺ T cells. Nature immunology. 2014; 15(11): 1055-63. Groenendyk Jody, Peng Zhenling, Dudek Elzbieta, Fan Xiao, Mizianty Marcin J, Dufey Estefanie, Urra Hery, Sepulveda Denisse, Rojas-Rivera Diego, Lim Yunki, Kim Do Han, Baretta Kayla, Srikanth Sonal, Gwack Yousang, Ahnn Joohong, Kaufman Randal J, Lee Sun-Kyung, Hetz Claudio, Kurgan Lukasz, Michalak Marek Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis. Science signaling. 2014; 7(329): ra54. Kim Kyun-Do, Srikanth Sonal, Tan Yossan-Var, Yee Ma-Khin, Jew Marcus, Damoiseaux Robert, Jung Michael E, Shimizu Saki, An Dong Sung, Ribalet Bernard, Waschek James A, Gwack Yousang Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. Journal of immunology (Baltimore, Md. : 1950). 2014; 192(1): 110-22. Srikanth Sonal, Kim Kyun-Do, Gwack Yousang Methods to measure cytoplasmic and mitochondrial Ca(2+) concentration using Ca(2+)-sensitive dyes. Methods in enzymology. 2014; 543(1): 1-20. Srikanth Sonal, Gwack Yousang Molecular regulation of the pore component of CRAC channels, Orai1. Current topics in membranes. 2013; 71(1): 181-207.