STAT1 and pathogens, not a friendly relationship

Abstract

STAT1 belongs to the STAT family of transcription factors, which comprises seven factors: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT1 is a 91 kDa protein originally identified as the mediator of the cellular response to interferon (IFN) alpha, and thereafter found to be a major component of the cellular response to IFNgamma. STAT1 is, in fact, involved in the response to several cytokines and to growth factors. It is activated by cytokine receptors via kinases of the JAK family. STAT1 becomes phosphorylated and forms a dimer which enters the nucleus and triggers the transcription of its targets. Although not lethal at birth, selective gene deletion of STAT1 in mice leads to rapid death from severe infections, demonstrating its major role in the response to pathogens. Similarly, in humans who do not express STAT1, there is a lack of resistance to pathogens leading to premature 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 steps of this pathway can be blocked or inhibited by proteins produced in infected cells. Interestingly, some pathogens, like the oncogenic Epstein-Barr virus, have evolved a strategy which uses STAT1 activation.

Fig. 1

Molecular structure and ribbon model of the STAT1 dimer. A: Schematic molecular organization of STAT1α and STAT1β. B: 3D structure of STAT1 (residues 135–712) (from reference [56]). C. Schematic rendering of the STAT1 dimer in its phosphorylated form showing the SH2 domains interacting with tyrosine 701 (Y–P) the DNA-binding domain (DBD) interacting with DNA and the cup-and-ball-like N-terminal domain (adapted from reference [83]).

Fig. 2

Mechanisms of activation of STAT1 in the cytoplasm following interferon receptor activation. A. Phosphorylation of STAT1 on tyrosine (Y) 701 by JAK1 and JAK2 following IFNγ stimulation. B. Phosphorylation of STAT1 on tyrosine (Y) 701 by JAK1 and TYK2 following stimulation by IFNα.

Fig. 3

Speculative model for the mechanism of STAT1 activation. Unphosphorylated dimers can form (left side of figure) by interaction of the N-terminal ends (marked N). When phosphorylated, the dimers form by interaction of SH2 domains with phosphotyrosine 701 (P-Y-701). Tetramers can also form by interaction of the N-terminal ends of the phosphorylated dimers, in two different conformations (adapted from reference [59]).

Fig. 4

Nucleo-cytoplasmic shuttling of STAT1. STAT1 becomes phosphorylated on tyrosine 701 in the cytoplasm and enters the nucleus by interaction of its dimer-specific NLS with importin α/β. Phosphorylated STAT1 interacts with its DNA targets; when released from DNA, STAT1 is dephosphorylated and can return to the cytoplasm involving interaction of the NES with CRM1. There is also a constitutive nucleo-cytoplasmic shuttle of unphosphorylated STAT1. (Adapted from [69]).

Fig. 5

Transcriptional complexes formed with STAT1 following treatment with IFNα and IFNγ. There are two major complexes: the ISGF-3 complex comprising STAT1, IRF9 and STAT2 which binds the ISRE DNA motif, and the GAF complex comprising a STAT1 homodimer which binds the GAS DNA motif.

Fig. 6

Components of antigen presentation by CMH1 whose expression is modulated by STAT1α. The figure depicts the antigen presenting machinery; the identified STAT1 targets are highlighted in bold.

Fig. 7

Mechanism of the modulation of IgM to IgG2A class switching in mice by STAT1. In mice, the class switching of Ig is under the control of STAT1 through its target T-bet.

Fig. 8

Modulation of p53 activity by STAT1α. A: STAT1α stabilises p53 by inhibiting Mdm2 expression, and potentiates the transcriptional activity of p53 by forming complexes at the promoter level. B: STAT1α promotes serine 15 and serine 20 phosphorylation of p53.

Fig. 9

Multiple points of inhibition of the IFN-STAT1 pathway by pathogens. The actions of several pathogens on the different steps of STAT1 activation are illustrated. In the cytoplasm: inhibition of phosphorylation (L. Donovani: Leishmania Donovani); trapping in high molecular weight complexes (hmw) (MV: Measles Virus); induction of degradation (SV: Simian Virus, HPIV: human parainfluenza virus). Inhibition of nuclear transfer (HCMV: human cytomegalovirus, KPNα: karyopherin α). Activation of STAT1β: (L. Mexicana: Leishmania Mexicana, M. Tuberculosis: Mycobacterium Tuberculosis, Pr: proteasome). Within the nucleus: dephosphorylation (HCV: human hepatitis C virus). Inhibition of CBP/p300 binding: (B. mellitensis: Brucella mellitensis). Inhibition of STAT1 following inhibition of the methyltransferase PRMT1 (protein arginine methyltransferase 1) (HBV: human hepatitis B virus, HCV: human hepatitis C virus, meth: methyl group) the putative target of PRMT1, PIAS1 (Protein Inhibitor of STAT1) is indicated. Inhibition of nuclear export.

Fig. 10

Proposed mechanism for the activation of STAT1 by the oncogenic protein LMP1 in Epstein-Barr-transformed lymphoblastoid cell lines. Activation of the oncoprotein LMP1 results in the activation of NF-κB, the induction of the expression of IFNs and their production by cells drives the constitutive activation of STAT1 (adapted from reference [318]).

Fig. 11

Actions of STAT1 in EBV-positive lymphoblastoid cells expressing LMP1. A: activation of the NF-κB pathway by LMP1 or the TNFR. B. Complex interaction of STAT1 with the LMP1-activated NF-κB pathway. 1: Induction by NF-κB of IFNα and γ production leading to STAT1 activation. 2: Inhibition of TRADD by STAT1α binding, leading to NF-κB inhibition. 3: Activation of STAT1 by IFNRs following its liberation from TRADD. 4 and 5: activation of the NF-κB pathway by LMP1.