Spic, a member of the ETS family of transcription factors, has diverse functions. In embryonic stem cells (ESCs), it marks ground state pluripotency, regulates one-carbon metabolism and histone methylation by controlling the flux of S-adenosyl methionine to S-adenosyl-L-homocysteine (SAM-to-SAH), and modulating histone marks such as H3R17me2 and H3K4me3 [1]. In macrophages, Toll-like receptor (TLR) signaling induces Spic expression via a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, it downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression. Also, interferon-gamma blocks its expression in a STAT1-dependent manner [2].

In Salmonella, SpiC (a related protein in the context of Salmonella) is required for the secretion of Salmonella Pathogenicity Island 2 type III secretion system proteins, and is necessary for the survival of Salmonella within macrophages. A Salmonella Pullorum spiC mutant shows increased safety and high immune protection, making it a potential live attenuated Salmonella vaccine candidate [3,4,5]. In zebrafish, Spic guides the in-situ generation of metaphocytes from local progenitors, and metaphocytes are the major IL-22BP-producing cells essential for barrier immunity [6].

In summary, Spic plays crucial roles in multiple biological processes including pluripotency regulation in ESCs, inflammation and iron metabolism in macrophages, Salmonella pathogenesis, and zebrafish barrier immunity. Studies using genetic models such as the Salmonella spiC mutant and in understanding its role in macrophage function contribute to our knowledge in infectious diseases and immune-related conditions.

References:

1. Mirzadeh Azad, Fatemeh, Struys, Eduard A, Wingert, Victoria, Stunnenberg, Hendrik G, Atlasi, Yaser. 2023. Spic regulates one-carbon metabolism and histone methylation in ground-state pluripotency. In Science advances, 9, eadg7997. doi:10.1126/sciadv.adg7997. https://pubmed.ncbi.nlm.nih.gov/37595034/

2. Alam, Zahidul, Devalaraja, Samir, Li, Minghong, Levine, Matthew H, Haldar, Malay. . Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages. In Cell reports, 31, 107825. doi:10.1016/j.celrep.2020.107825. https://pubmed.ncbi.nlm.nih.gov/32610126/

3. Yu, Xiu-Jun, Ruiz-Albert, Javier, Unsworth, Kate E, Liu, Mei, Holden, David W. . SpiC is required for secretion of Salmonella Pathogenicity Island 2 type III secretion system proteins. In Cellular microbiology, 4, 531-40. doi:. https://pubmed.ncbi.nlm.nih.gov/12174087/

4. Geng, Shizhong, Qian, Shanshan, Pan, Zhiming, Chen, Xiang, Jiao, Xinan. . Preparation of Monoclonal Antibodies Against SpiC Protein Secreted by T3SS-2 of Salmonella spp. In Monoclonal antibodies in immunodiagnosis and immunotherapy, 34, 432-5. doi:10.1089/mab.2015.0035. https://pubmed.ncbi.nlm.nih.gov/26683183/

5. Wang, Yaonan, Huang, Cuiying, Tang, Juan, Jiao, Xin'an, Geng, Shizhong. 2021. Salmonella Pullorum spiC mutant is a desirable LASV candidate with proper virulence, high immune protection and easy-to-use oral administration. In Vaccine, 39, 1383-1391. doi:10.1016/j.vaccine.2021.01.059. https://pubmed.ncbi.nlm.nih.gov/33551301/

6. Zhao, Changlong, Li, Yunbo, Tang, Jinlin, Lin, Xi, Wen, Zilong. 2023. Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity. In Cell reports, 42, 112483. doi:10.1016/j.celrep.2023.112483. https://pubmed.ncbi.nlm.nih.gov/37148242/