Lythe, G. | Search bioRxiv

bioRxiv2021

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27R, as the main dynamical processes contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with Systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

bioinformatics↗

bioRxiv2020

Fusion and fission events regulate endosome maturation and viral escape

Many intra-cellular processes rely on transport by endosomes. Recent experimental techniques have provided insights into organelle maturation and its specific role in, for instance, the ability of a virus to escape an endosome and release its genetic material in the cytoplasm. Endosome maturation and dynamics depend on GTPases called Rabs, found on their membrane. Here, we introduce a mathematical framework, combining coagulation and fragmentation of endosomes with two variables internal to each organelle, to model endosomes as intra-cellular compartments characterised by their levels of (active) Rab5 and Rab7. The key element in our framework is the "per-cell endosomal distribution" and its its dynamical equation or Boltzmann equation. The Boltzmann equation, then, allows one to deduce simple equations for the total number of endosomes in a cell, and for the mean and standard deviation of the Rab5 and Rab7 levels. We compare our solutions with experimental data sets of Dengue viral escape from endosomes. The relationship between endosomal Rab levels and pH suggests a mechanism which can account for the observed variability in viral escape times, which in turn regulate the viability of a viral intra-cellular infection. Author summaryEndosomes are intra-cellular receptacle-like organelles, which transport endocytosed cargo upon internalisation from the plasma membrane. These early endosomes, also known as sorting endosomes, mature to late endosomes, with a lower pH than early ones, as a consequence of the intricate dynamics of a family of molecules called Rabs. Viruses exploit this endosomal pH drop to their advantage. Here we bring together experimental data on Dengue viral escape times from endosomes and a novel mathematical framework inspired by the theory of droplet coalescence, to improve our understanding of endosome maturation, and in turn to quantify the large variability of viral escape times. This mathematical framework can easily be generalised to model the dynamics of other intra-cellular organelles, such as mitochondria or the endoplasmic reticulum.

systems biology↗