Different STAT Transcription Complexes Drive Early and Delayed Responses to Type I IFNs

Abstract

Interferons, which transduce pivotal signals through signal transducer and activator of transcription (Stat)1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Whereas the ability of IFN-γ to impede L. pneumophila growth is fully dependent on Stat1, IFN-α/β unexpectedly suppresses L. pneumophila growth in both Stat1 and Stat2 deficient macrophages. New studies demonstrating that the robust response to IFN-α/β is lost in Stat1-Stat2 double knockout macrophages, suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response towards L. pneumophila. Since the ability of IFN-α/β to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-α/β in the absence of Stat1. These studies reveal that IFN-α/β is able to drive the formation of a Stat2 and IRF9 complex that drives the expression of a subset of IFN stimulated genes (ISGs), but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1 dependent responses.

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

“…The same was the case when STAT2 was blocked: there was an increase in STAT1 activation but in this case upregulation of STAT1 did not prevent inhibition of the downstream effects of IFNα (Figs 3 and 4). Primary murine macrophages deficient in STAT1, when exposed to Legionella pneumophila in the presence of type I IFNs, induce a complex between STAT2 and IRF9 that triggers a potent but delayed IFN response against the bacteria [33]. This indicates that both STATs are functionally redundant in macrophages [33].…”

“…Primary murine macrophages deficient in STAT1, when exposed to Legionella pneumophila in the presence of type I IFNs, induce a complex between STAT2 and IRF9 that triggers a potent but delayed IFN response against the bacteria [33]. This indicates that both STATs are functionally redundant in macrophages [33]. Our present data, however, suggest that the roles of STAT1 and STAT2 are not redundant in beta cells, as the observed increase in STAT1 activation is not sufficient to compensate for the lack of STAT2.…”

“…STAT2 dimerises with IRF9 in the absence of STAT1; this dimer subsequently binds to the IFN-stimulated response element (ISRE) and mediates downstream signal transduction [33]. Knockdown of IRF9 (≥60% at mRNA and ≥80% at protein level; Fig.…”

Impact of host genetic polymorphisms on vaccine induced antibody response

“…35,36 The immune system shows features of robust systems such as functional redundancy of genes and proteins. [37][38][39] For example, a mutation in IFN-a1 (IFNA1) may affect its binding affinity to a receptor, but it has many paralogues, which are themselves potent alpha interferons (IFN-a2-14). 37 On the other hand, mutations in the NF-kB signaling pathway or several mutations in HLA molecules has been linked to diseases such as Crohn's disease and other autoimmune disorders.…”

Integrity of a HPV11 infection cell model and identification of (-)-Epigallocatechin-3-gallate as a potential HPV11 inhibitor

“…The type-I IFNs, including IFN-α and IFN-β, have antiviral, antiproliferative, antiangiogenic, and immunostimulatory properties. They mediate their biological responses through the STAT family of transcription factors [21, 22]. When infected with HPVs, the HPV oncogenes interact with components of IFN signaling pathways and inhibit the IFN-α-mediated signaling.…”