Role of STAT2 in the Alpha Interferon Signaling Pathway

Abstract

(22,26,43,44), and transcription factor subunits called STATs (signal transducers and activators of transcription) (8, 39). Phosphorylated STATs, which also contain Src homology 2 (SH2) domains, associate to form homo-and heterodimers (40, 51). These dimers, with or without additional cofactors, migrate to the nucleus, where they activate the transcription of IFN-responsive genes (5).IFN-␣ and -␤ induce formation of the transcription factor IFN-stimulated gene factor 3 (ISGF3) (4,20). The binding sites on DNA for ISGF3, called IFN-stimulated response elements (ISREs), are found near promoters of most IFN-␣/␤-responsive genes (7,19,31,33,34,48). The ISGF3 transcription factor is an oligomeric protein with three subunits: STAT1, STAT2, and a 48-kDa DNA-binding protein (9,10,38,46). STAT1 exists in two alternatively spliced forms of 91 kDa (STAT1␣) and 84 kDa (STAT1␤); either is capable of participating in ISGF3 formation (27). STAT2 is a 113-kDa protein having approximately 40% homology with STAT1␣ (10). Unlike IFN-␣/␤, IFN-␥ triggers the phosphorylation on tyrosine of STAT1 but not STAT2 (41), leading to formation of the gamma-activated transcription factor GAF, which binds to the gamma-activated sequences (GAS) (6,21,42). GAF is formed when STAT1␣ subunits dimerize through reciprocal SH2 domain-phosphotyrosine interactions (40). Phosphorylation of STAT1 and formation of STAT1 homodimers can also be activated by IFN-␣. Before the STAT proteins were recognized, this IFN-␣-activated factor was called AAF (6).Unphosphorylated STAT1␣ binds to a specific phosphotyrosine near the C terminus of the IFN-␥ receptor ␣ chain (12). Phosphorylation of this tyrosine upon binding of IFN-␥ to the receptor is an early step in the IFN-␥ signaling pathway, creating a binding site for the unphosphorylated transcription factor subunit in proximity to the receptor-bound tyrosine kinases JAK1 and JAK2 (26, 49). The IFN-␣ receptor may employ a similar mechanism. However, although phosphorylation of the IFN-␣ receptor has been observed (30), the site is not yet known.Genetic studies using mutant cell lines unresponsive to the IFNs (17,24,29,49) have established the functional importance of JAKs and STATs in the pathways. Two JAK family kinases, TYK2 (47) and JAK1 (26), as well as STAT1 (27) and the 48-kDa DNA-binding protein (17) are required for the response of most genes to IFN-␣. However, the situation is somewhat complex in that mutants lacking TYK2 retain a weak response to , probably mediated by formation of ISGF3 (15). Furthermore, some genes (IRF-1, for example) respond to IFN-␣/␤ independently of ISGF3, utilizing AAF to activate a GAS-like element (6, 13). The availability of mutant cell lines lacking the individual proteins of ISGF3 allows analysis of the function of each protein separately. Study of U3A cells, which lack STAT1␣ and -␤, has shown that STAT1␣ (but not STAT1␤) is required in the IFN-␥ pathway, that either STAT1␣ or STAT1␤ can function in the IFN-␣ pathway, and that Y-701 (the phosphorylation site in STAT1) and R...

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

“…Notably, IFN-l1 signaling involves the phosphorylation of STAT2, considered a defining characteristic of Type-I responses. 40,41 Furthermore, interferon response genes such as MxA and 5 0 3 0 OAS are activated 2 and subjected to typical regulatory mechanisms. 11 Although the IFN-l receptor is widely expressed, 2,3 expression of the ligand is tightly controlled and takes place after viral infection 2,17 or stimulation via many of the Toll-like receptors (TLRs), 15 a process that is elevated by IFN-a.…”

Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones

“…Antibodies used in the present study were as follows: anti-Bcl-2 (Dako, Glostrup, Denmark), anti-Bcl-x (Santa Cruz Biotechnology, Santa Cruz, CA), anti-Bax (Santa Cruz Biotechnology), anti-P53 (Dako), anti-c-Myc (Santa Cruz Biotechnology), anti-Rb (Santa Cruz Biotechnology), anti-STAT1, anti-STAT2, and anti-STAT3 (the latter three from Transduction Laboratories, Lexington, KT). method with empty pME18S expression vector (kindly provided by Dr K. Maruyama, Tokyo Medical and Dental University, Tokyo, Japan) or that containing a full-length STAT2 cDNA (kindly provided by Dr J. E. Darnell, Jr., The Rockefeller University, New York, NY) [23][24][25]. The transfected T cell clones were maintained in culture for 36 h. Thereafter, these clones were induced to die by growth factor deprivation apoptosis.…”

Identification of alternative splicing form of Stat2

“…IFN-~ signaling involves phosphorylation of Statl [2] and Stat2 [3,4] through Jakl [5] and Tyk2 [6], leading to formation of the transcription factor IFN-stimulated gene factor 3 (ISGF3) [7,8] that binds to the IFN-stimulated response elements (ISREs). The ISGF3 transcription factor is composed of three subunits: Statlot/13 [2], Stat2 and p48 DNA binding protein [9].…”