👤 François Mariotti

To assess the cross-talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analyzed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic human airway epithelium (HAE). The results indicated that immune cells failed to inhibit SARS-CoV-2 replication in the HAE model. In contrast, immune cells strongly affected the inflammatory profile induced by SARS-CoV-2 infection, dampening the production of several immunoregulatory/inflammatory signals (e.g., IL-35, IL-27, and IL-34). Moreover, these mediators were found inversely correlated with innate immune cell frequency (NK and γδ T cells) and directly with CD8 T cells. The enriched signals associated with NK and CD8 T cells highlighted the modulation of pathways induced by SARS-CoV-2 infected HAE. These findings are useful to depict the cell-cell communication mechanisms necessary to develop novel therapeutic strategies aimed to promote an effective immune response. Show less

The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β-catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β-catenin destruction complex, and targets it for degradation, thereby fine-tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt-dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β-catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re-tune Wnt/β-catenin signalling in colorectal cancer cells. This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. Show less

The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. Show less