Expression of the V proteins by the simian virus 5 (SV5) and HPIV2 by the human virus type 2 (HPIV2) highjacks the polyubiquitinylation pathways of the cell and induces polyubiquitylation of STAT1 and STAT2 resulting in their degradation by the proteasome, an action that is inhibited by proteasome inhibitors such as lactacystine or MG132 [205]. death. This indicates a key, non-redundant function of STAT1 in the defence against pathogens. Thus, to successfully infect organisms, bacterial, viral or parasitic pathogens must overcome the activity of STAT1, and almost all the actions of this pathway can be blocked or?inhibited by proteins produced in infected cells. Interestingly, some pathogens, like the oncogenic EpsteinCBarr virus, have evolved a strategy which uses STAT1 activation. 1.?Activation of STAT1 1.1. Molecular structure of STAT1 STAT1 was initially identified as an interferon (IFN) mediator [1], [2], and thereafter found to be a major component of the cellular response to IFN. STAT1 belongs to a family of transcription factors comprising STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 [3], [4]. The transcript of STAT1 undergoes alternative splicing, resulting in two isoforms: STAT1 (91?kDa) and STAT1 (84?kDa) [5]. The isoform possesses a complete transactivation domain name (TAD) and two major phosphorylated sites: tyrosine 701 and serine 727. The isoform is usually shorter and lacks p53 and MDM2 proteins-interaction-inhibitor chiral most of the TAD, including serine 727; both isoforms contain an SH2 domain name, a DNA-binding domain name (DBD) and an N-terminal domain name. Diffraction studies show?STAT1 crystals dimers forming through interaction of the phosphotyrosine 701 p53 and MDM2 proteins-interaction-inhibitor chiral and the SH2 domain name (Fig.?1 ). Open in a separate window Fig.?1 Molecular structure and ribbon model of the STAT1 dimer. A: Schematic molecular organization of STAT1 and STAT1. B: 3D structure of STAT1 (residues 135C712) (from reference [56]). C. Schematic rendering of the STAT1 dimer in its phosphorylated form showing the SH2 domains interacting with tyrosine 701 (YCP) the DNA-binding domain name (DBD) interacting with DNA and the cup-and-ball-like N-terminal domain name (adapted from reference [83]). 1.2. Stimuli that activate STAT1 STAT1 is an essential effector of IFNs. Following activation of the IFN receptor, its two subunits, IFNGR1 and IFNGR2 which are isolated in the absence of stimulation [6], [7], [8] become assembled [9], [10]. The two JAK family kinases, JAK1 and JAK2, which are constitutively bound to the inactive chains of the receptor, become activated, resulting in the autophosphorylation of JAK2, which in turn phosphorylates JAK1. The two kinases then phosphorylate the IFNR subunits, forming STAT1 binding sites [11]. STAT1 Rabbit Polyclonal to OR51B2 binds via its SH2 domain name [12] and is phosphorylated on tyrosine 701 [13], [14] (Fig.?2 A). The activation of STAT1 following IFN triggering is usually somewhat different. The subunit IFNAR2 of the IFNR forms a complex with TYK2 and STAT2 in the absence of stimulation by IFN, and the subunit IFNAR1 is usually associated to JAK1 [15], [16]. Following conversation of IFN with the two subunits of its receptor [17], [18], JAK1 and TYK2 do not autophosphorylate, but instead phosphorylate one another [19], and subsequently phosphorylate both IFNAR1 and IFNAR2 [20], as well as the tyrosine 690 of STAT2 to which STAT1 binds through its SH2 domain name, and STAT1 on tyrosine 701. The phosphorylated STAT1/STAT2 dimer is usually then released from the IFNAR2 chain (Fig.?2B). STAT1 is also activated in response to several interleukins, including IL2 and IL6 (see Table 1 and references [21], [22], [23], [24]); and in response to growth factors including EGF and PDGF (see Table 1 and reference [21]). Oncostatin M and growth hormone also activate STAT1: this occurs through activation of JAK2 which binds to signaling proteins such as Grb2, Ras or Raf [25], [26], [27]. Other factors such as angiotensin II [28], HGF [29] and TNF [30] activate STAT1. However, they appear to do so without inducing its nuclear translocation nor activating p53 and MDM2 proteins-interaction-inhibitor chiral its DNA-binding, suggesting cytoplasmic functions for STAT1. Open in a separate window Fig.?2 Mechanisms of activation of STAT1 in the p53 and MDM2 proteins-interaction-inhibitor chiral cytoplasm following interferon receptor activation. A. Phosphorylation of STAT1 on tyrosine (Y) 701 by JAK1 and JAK2 following IFN stimulation. B. Phosphorylation of STAT1 on tyrosine (Y) 701 by JAK1 and TYK2 following.