Stat2, short for Signal transducer and activator of transcription 2, is an essential transcription factor exclusive to type I and III interferon (IFN) signaling pathways. It plays a crucial role in immune responses to extracellular and intracellular stimuli, including inflammatory reactions, foreign material invasion, and cancer initiation [2]. Its activation by tyrosine phosphorylation triggers dimerization, nuclear translocation, and transcriptional activation of IFN-stimulated genes [7].

In macrophages, Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation. Knockdown of Drp1, which is regulated by Stat2-boosted phosphorylation at serine 616, blunts LPS-induced mitochondrial mass increase and pro-inflammatory differentiation in macrophages [1]. In experimental colitis, IL-20 controls colitis and mucosal healing by interfering with the IFN/Stat2 death-signaling pathway in intestinal epithelial cells (IECs). Stat2ΔIEC mice, lacking Stat2 in IECs, are less susceptible to experimental colitis [3]. In ovarian cancer, the Fibrillin-1/VEGFR2/Stat2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis [4]. Zika virus NS5 protein degrades Stat2 through the CRL3 E3 ubiquitin ligase-mediated pathway, inhibiting type I interferon signaling [5]. In colorectal cancer, circCAPRIN1 binds to Stat2 to promote tumor progression and lipid synthesis by upregulating ACC1 expression [6]. Human inherited complete Stat2 deficiency underlies inflammatory viral diseases, with patients showing impaired expression of IFN-stimulated genes and control of in vitro viral infections, along with severe viral infections and hyperinflammation [8].

In summary, Stat2 is a key transcription factor in IFN signaling pathways, playing important roles in various biological processes and diseases. Studies using gene-knockout or conditional-knockout mouse models, like Stat2ΔIEC mice, have revealed its functions in macrophage pro-inflammatory differentiation, colitis, viral diseases, and cancer-related processes such as chemoresistance and tumor progression. Understanding Stat2's functions can potentially lead to new therapeutic approaches for treating inflammatory and infectious diseases, as well as cancer [1,3,4,5,6,8].

References:

1. Yu, Weihua, Wang, Xin, Zhao, Jiuzhou, Li, Wenli, Hai, Chunxu. 2020. Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. In Redox biology, 37, 101761. doi:10.1016/j.redox.2020.101761. https://pubmed.ncbi.nlm.nih.gov/33080440/

2. Lee, Cheol-Jung, An, Hyun-Jung, Cho, Eun Suh, Lee, Hye Suk, Cho, Yong-Yeon. 2020. Stat2 stability regulation: an intersection between immunity and carcinogenesis. In Experimental & molecular medicine, 52, 1526-1536. doi:10.1038/s12276-020-00506-6. https://pubmed.ncbi.nlm.nih.gov/32973222/

3. Chiriac, Mircea Teodor, Hracsko, Zsuzsanna, Günther, Claudia, Becker, Christoph, Neurath, Markus F. 2024. IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling. In Gut, 73, 282-297. doi:10.1136/gutjnl-2023-329628. https://pubmed.ncbi.nlm.nih.gov/37884352/

4. Wang, Ziliang, Chen, Wei, Zuo, Ling, Wang, Husheng, Sun, Huizhen. 2022. The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells. In Cancer communications (London, England), 42, 245-265. doi:10.1002/cac2.12274. https://pubmed.ncbi.nlm.nih.gov/35234370/

5. Ren, Wenlin, Fu, Chonglei, Zhang, Yu, Yao, Jun, Ding, Qiang. 2024. Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2403235121. doi:10.1073/pnas.2403235121. https://pubmed.ncbi.nlm.nih.gov/39145933/

6. Yang, Yufei, Luo, Dakui, Shao, Yang, Wang, Ziliang, Li, Xinxiang. 2022. circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer. In Cancer communications (London, England), 43, 100-122. doi:10.1002/cac2.12380. https://pubmed.ncbi.nlm.nih.gov/36328987/

7. Steen, Håkan C, Gamero, Ana M. 2013. STAT2 phosphorylation and signaling. In JAK-STAT, 2, e25790. doi:10.4161/jkst.25790. https://pubmed.ncbi.nlm.nih.gov/24416652/

8. Bucciol, Giorgia, Moens, Leen, Ogishi, Masato, Casanova, Jean-Laurent, Meyts, Isabelle. 2023. Human inherited complete STAT2 deficiency underlies inflammatory viral diseases. In The Journal of clinical investigation, 133, . doi:10.1172/JCI168321. https://pubmed.ncbi.nlm.nih.gov/36976641/