Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response.

Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting transcription.

Antagonism between viral infection and innate immunity at the single-cell level.

When infected with a virus, cells may secrete interferons (IFNs) that prompt nearby cells to prepare for upcoming infection. Reciprocally, viral proteins often interfere with IFN synthesis and IFN-induced signaling. We modeled the crosstalk between the propagating virus and the innate immune response using an agent-based stochastic approach.

A plausible identifiable model of the canonical NF-κB signaling pathway.

An overwhelming majority of mathematical models of regulatory pathways, including the intensively studied NF-κB pathway, remains non-identifiable, meaning that their parameters may not be determined by existing data. The existing NF-κB models that are capable of reproducing experimental data contain non-identifiable parameters, whereas simplified models with a smaller number of parameters exhibit dynamics that differs from that observed in experiments. Here, we reduced an existing model of the canonical NF-κB pathway by decreasing the number of equations from 15 to 6.

Respiratory Syncytial Virus Protects Bystander Cells against Influenza A Virus Infection by Triggering Secretion of Type I and Type III Interferons.

We observed the interference between two prevalent respiratory viruses, respiratory syncytial virus (RSV) and influenza A virus (IAV) (H1N1), and characterized its molecular underpinnings in alveolar epithelial cells (A549). We found that RSV induces higher levels of interferon beta (IFN-β) production than IAV and that IFN-β priming confers higher-level protection against infection with IAV than with RSV. Consequently, we focused on the sequential infection scheme of RSV and then IAV.

Cell fate in antiviral response arises in the crosstalk of IRF, NF-κB and JAK/STAT pathways.

The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS.

Information processing in the NF-κB pathway.

The NF-κB pathway is known to transmit merely 1 bit of information about stimulus level. We combined experimentation with mathematical modeling to elucidate how information about TNF concentration is turned into a binary decision. Using Kolmogorov-Smirnov distance, we quantified the cell's ability to discern 8 TNF concentrations at each step of the NF-κB pathway, to find that input discernibility decreases as signal propagates along the pathway.

Importins promote high-frequency NF-κB oscillations increasing information channel capacity.

Background: Importins and exportins influence gene expression by enabling nucleocytoplasmic shuttling of transcription factors. A key transcription factor of innate immunity, NF-κB, is sequestered in the cytoplasm by its inhibitor, IκBα, which masks nuclear localization sequence of NF-κB. In response to TNFα or LPS, IκBα is degraded, which allows importins to bind NF-κB and shepherd it across nuclear pores.

Calcyclin Binding Protein/Siah-1 Interacting Protein Is a Hsp90 Binding Chaperone.

The Hsp90 chaperone activity is tightly regulated by interaction with many co-chaperones. Since CacyBP/SIP shares some sequence homology with a known Hsp90 co-chaperone, Sgt1, in this work we performed a set of experiments in order to verify whether CacyBP/SIP can interact with Hsp90. By applying the immunoprecipitation assay we have found that CacyBP/SIP binds to Hsp90 and that the middle (M) domain of Hsp90 is responsible for this binding.

Nuclear translocation of Sgt1 depends on its phosphorylation state.

Recently we have shown that the Sgt1 (suppressor of G2 allele of Skp1) protein translocates to the nucleus due to heat shock and that the Ca(2+)-bound form of S100A6 is required for Sgt1 translocation (Prus and Filipek, 2010). In this work we studied the influence of Sgt1 phosphorylation on nuclear translocation. By means of two-dimensional (2D) electrophoresis we showed that in the protein extract of heat-shocked human epidermoid carcinoma (HEp-2) cells a higher level of a basic, most probably non-phosphorylated, form of Sgt1 can be detected.

S100A6 mediates nuclear translocation of Sgt1: a heat shock-regulated protein.

Sgt1 was originally identified in yeast as a suppressor of the Skp1 protein. Later, it was found that Sgt1 is present in plant and mammalian organisms and that it binds other ligands such as S100A6, a calcium-binding protein. In this work we show that in HEp-2 cells Sgt1 translocates to the nucleus due to heat shock.

Sgt1 has co-chaperone properties and is up-regulated by heat shock.

The Sgt1 protein is a binding partner of heat shock proteins such as Hsp90, Hsp70 or Hsc70. In this work we show that the level of Sgt1 is increased in HEp-2 cells exposed to heat shock or radicicol. The citrate synthase aggregation assay shows that Sgt1 attenuates aggregation of the enzyme induced by increased temperature as efficiently as p23, a known co-chaperone of Hsp90.