STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway

Journal of biosciences

Jinbo Yang1 2¹  Ning Zhu¹  Xing Chen¹  Jie Shi¹  Ximing Xu¹  Qin Wang1¹  Jianxin He¹  Yuxin Wang¹  Jing Zhang¹  Wenhua Zhang¹  Yuping Du¹ 

[1] School of Life Science, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China$$

关键词: Hyper-IgE syndrome;    IL-6;    Jak/STAT3 signalling;    STAT3 mutation;   

DOI  :  

来源: Indian Academy of Sciences

【 摘 要 】

Of all the causes identified for the disease hyper-immunoglobulinemia E syndrome (HIES), a homozygous mutation in tyrosine kinase2 (TYK2) and heterozygous mutations in STAT3 are implicated the defects in Jak/STAT signalling pathway in the pathogenesis of HIES. Mutations of STAT3 have been frequently clinically identified in autosomal-dominant (AD) HIES patients’ cells, and therefore, the genotype of STAT3 has been associated with the phenotype of HIES. Here, we conducted studies on the functional loss of the seven specific STAT3 mutations correlated with ADHIES. Using STAT3-null human colon carcinoma cell line A4 cells, we generated seven mutants of STAT3 bearing single mutations clinically identified in AD-HIES patients’ cells and studied the functional loss of these mutants in IL-6-Jak/STAT3 signalling pathway. Our results show that five STAT3 mutants bearing mutations in the DNA-binding domain maintain the phosphorylation of Tyr705 and the ability of dimerization while the other two with mutations in SH2 domain are devoid of the phosphorylation of Try705 and abrogate the dimerization in response to IL-6. The phosphorylation of Ser727 in these mutants shows diversity in response to IL-6. These mutations eventually converge on the abnormalities of the IL-6/Gp130/Jak2-mediated STAT3 transactivation on target genes, indicative of the dysregulation of JAK/STAT signalling present in HIES.

【 授权许可】

Unknown