The Ying and Yang of STAT3 in Human Disease

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

Keywords: Hyper-IgE syndrome; Job syndrome; STAT3; gain-of-function; monogenic autoimmunity.

Fig. 1. Schematic of the STAT3 protein showing the location of mutations reported to cause human disease

STAT3 is divided into 6 domains: the N-terminal domain (NT), coiled-coil domain (C-C), DNA binding domain (DBD), linker domain (L), Src-homology 2 (SH2) domain and transactivation domain (TA). Mutations shown above the figure represent missense mutations and the resulting amino acid changes, while mutations shown below the figure are deletions, duplications or intronic mutations represented in nucleotide nomenclature [–, , , , , , –, , , –103]. Loss-of-function (LOF) mutations found in Hyper-IgE syndrome are indicated in green, those germline mutations reported in STAT3 gain-of-function (GOF) are indicated in black, and the somatic, GOF mutations reported in malignancy, including LGL leukemia, are reported in blue. Malignancy-associated, somatic GOF mutations are clustered in the SH2 domain, whereas germline, GOF mutations are found throughout the protein. Most LOF mutations cluster in the DBD (42%) and SH2 domain (40%), where the highest number of unique LOF mutations are also found in the SH2 domain hot spot. The highest frequency LOF mutations representing the most patients are R382Q/W and V637M [39]. The intronic mutations surrounding exon 12 in the DBD (at c.1110 and c.1139) lead to a deletion of this short exon, D371_G380. The TA domain mutation c.2101+2332_oSTAT3:c.2257+772del3933bp leads to the loss of exons 22 and 23, which are replaced with only a lysine residue