Stat2 stability regulation: an intersection between immunity and carcinogenesis

Abstract

Signal transducer and activator of transcription (STAT2) is a member of the STAT family that plays an essential role in immune responses to extracellular and intracellular stimuli, including inflammatory reactions, invasion of foreign materials, and cancer initiation. Although the majority of STAT2 studies in the last few decades have focused on interferon (IFN)-α/β (IFNα/β) signaling pathway-mediated host defense against viral infections, recent studies have revealed that STAT2 also plays an important role in human cancer development. Notably, strategic research on STAT2 function has provided evidence that transient regulatory activity by homo- or heterodimerization induces its nuclear localization where it to forms a ternary IFN-stimulated gene factor 3 (ISGF3) complex, which is composed of STAT1 and/or STAT2 and IFN regulatory factor 9 (IEF9). The molecular mechanisms of ISGF3-mediated ISG gene expression provide the basic foundation for the regulation of STAT2 protein activity but not protein quality control. Recently, previously unknown molecular mechanisms of STAT2-mediated cell proliferation via STAT2 protein quality control were elucidated. In this review, we briefly summarize the role of STAT2 in immune responses and carcinogenesis with respect to the molecular mechanisms of STAT2 stability regulation via the proteasomal degradation pathway.

Fig. 1. Basic molecular structure of the SCF complex.

The SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex is the most well-characterized cullin RING ubiquitin ligase (CRL). Since the F-box proteins contain approximately 69 different components that bind to SKP1, many different combination of specific SCF complex formation are possible with a selective substrate and depending on the cellular context. Moreover, eight cullin proteins add a more complicated combinational probability for tissue, developmental, and stimuli specificities. Finally, the ubiquitination in mono-, multi-, single-chain, poly-chain, and branched-chain patterns might indicate precise regulation of the cellular functions of proteins by reflecting diverse cell conditions.

Fig. 2. Representative regulatory mechanisms of STAT2-mediated ISG expression.

a ISG expression under normal physiological conditions. Without stimulation, STAT2 forms a tetramer complex with other STAT family members, including STAT1, 3, and 6, through their N-terminal domains, resulting in an anti-parallel structure. The complex induces basal expression of target genes. b ISG expression under physiological conditions after viral infection. When cells are infected with viruses, activated JAK1- and TYK2-mediated phosphorylation of STAT2 at tyrosine residues triggers the formation of a SH2–pTyr interaction-mediated homo- or heterodimer complex, which associates with IRF9 and results in the formation of the ISGF3 complex. The ISGF3 complex plays a key role in target gene expression in response to viral infection.

Fig. 3. Characteristics and roles of STAT2 domains.

Each STAT2 domain plays a specific role in homo- or heterodimerization and ISG expression. The diverse stimuli from outside or inside cells induce posttranslational modifications such as phosphorylation and ubiquitination to induce structural changes, parallel or anti-parallel oriented homo- or heterodimers, nuclear or cytosolic localization, and DNA binding.

Fig. 4. New paradigm for the regulation of STAT2 protein in melanoma formation.

In normal cells, STAT2 protein levels are maintained at low levels. When cells are stimulated by UV, especially UVB, GSK3α/β phosphorylates STAT2 at the DBD, which recruits the SCF^FBXW7 complex to form the SCF^FBXW7–STAT2 complex. FBXW7 catalyzes K48 STAT2 polyubiquitination, resulting in a reduction in STAT2 protein levels via the proteasomal degradation pathway. Thus, cell proliferation at the acute stage is initially suppressed after UVB irradiation. However, in cancer cells with FBXW7 mutation(s), higher STAT2 protein levels are sustained compared to that of normal cells, resulting in the induction of cell proliferation.