STAT1

Fig1. Structures of STAT1α and STAT1β. (Manlio Tolomeo, 2022)

What is STAT1 Protein?

STAT1 gene (signal transducer and activator of transcription 1) is a protein coding gene which situated on the long arm of chromosome 2 at locus 2q32. The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. The STAT1 protein is consisted of 750 amino acids and STAT1 molecular weight is approximately 87.3 kDa.

What is the Function of STAT1 Protein?

STAT1 protein is a member of the signal transduction and transcriptional activator family, which plays a key role in the signal response of cytokines and growth factors. STAT1 is activated mainly by phosphorylation of its C-terminal tyrosine and serine residues, forming dimers and translocating into the nucleus to regulate the expression of target genes. The signaling pathway of STAT1 depends on interferon (IFN) signaling, which is involved in the regulation of cell anti-proliferation, apoptosis, cell proliferation, negative regulation of cell cycle, inhibition of tumor angiogenesis, and weakening of tumor migration and invasion. In addition, STAT1 also plays a role in the mechanism of the formation of CD8 T cell responses in vivo, influencing the proliferation of CD8 T cells by regulating STAT1-dependent signaling pathways. The function of STAT1 is not limited to tumor suppression; its overactivation may promote the proliferation and drug resistance of tumor cells in some cases.

STAT1 Related Signaling Pathway

STAT1 is a major effector molecule in interferon signaling pathways, specifically type I and Type II interferon (IFN-α/β and IFN-γ) signaling pathways. STAT1 is involved in the signaling of various cytokines, such as IL-6, IL-10, etc. These cytokines activate JAKs through specific receptor binding, thereby activating STAT1 and regulating the proliferation, differentiation and function of immune cells. STAT1 can form heterodimers with other STAT family members or homologous dimers with itself to participate in complex signal regulation networks. STAT1 activity is regulated by negative regulators including the SOCS protein family, PIAS proteins, and tyrosine phosphatase, which inhibit the overactivation of the JAK-STAT signaling pathway through different mechanisms.

STAT1 Related Diseases

Abnormal activity of the STAT1 protein has been associated with a variety of diseases, especially viral infections and immunodeficiency diseases associated with interferon signaling pathways, such as chronic viral infections, certain types of cancer (due to its role in cell proliferation and anti-tumor immunity), autoimmune diseases (such as systemic lupus erythematosus, due to its role in immune regulation), and autoimmune diseases (such as systemic lupus erythematosus). And certain primary immunodeficiency diseases (such as inherited STAT1 deficiency due to mutations in the STAT1 gene), in which dysfunction of STAT1 may lead to increased susceptibility to pathogens, abnormal immune system function, or impairment of tumor surveillance mechanisms.

Fig2. Tumour promoting functions of STAT1. (Katrin Meissl, 2017)

Bioapplications of STAT1

Due to its central role in the interferon signaling pathway, STAT1 protein's relevant off-the-shelf applications are mainly concentrated in the field of antiviral and anti-tumor therapy. For example, interferon therapy uses STAT1-mediated signaling to enhance the body's antiviral response and immune surveillance, and is widely used in the treatment of chronic viral infections such as hepatitis B and C. In addition, the activation status of STAT1 has also been used as a biomarker to assess treatment response and prognosis in certain cancers. In immunomodulatory therapy, the function of STAT1 is indirectly affected by drugs that target the JAK-STAT pathway for the treatment of autoimmune diseases and certain types of cancer. However, due to the broad role of STAT1 in multiple biological processes, these treatments need to carefully balance their efficacy against possible side effects.