European Medical Journal (Sep 2019)
Systemic Sclerosis: The Role of YAP/TAZ in Disease Pathogenesis
Abstract
Systemic sclerosis (SSc) is a systemic autoimmune condition of unknown cause. Yes-Associated Protein/Tafazzin (YAP/TAZ) are transcriptional coactivators previously demonstrated to be involved in cellular stretch biology, and form the principal effector molecules of the Hippo signalling pathway. The association between YAP/TAZ and stretch is contingent upon their cytoplasmic localisation (with nuclear translocation, the cell adopts a relaxed state). The author weighs the evidence for a central role for YAP/TAZ signalling in scleroderma spanning the major clinical features of the condition. Several of the features unique to SSc are mediated by cytoplasmic localisation of YAP/TAZ, including the stretch phenotype (through binding to NF-2), arterial lumenal obliteration (through their binding to angiomotin), the promotion of hypergammaglobulinaemia (via feedback to the upstream Hippo signalling molecule Mammalian Ste20-like Kinase 1), and the induction of B-Lymphocyte-Induced Maturation Protein-1 leading to the adoption of Th2 lineage, prominent in SSc. One observes that the induction of the fibrotic phenotype of scleroderma is mediated through GLI1/GLI2 (the effector molecules of the Hedgehog pathway). GLI1/GLI2 are induced to reciprocally enter the nucleus when YAP/TAZ is intracytoplasmic. The latter explains the characteristically increased connective tissue growth factor 2 and endothelin-1 expression. In this article, the author references some examples of the role of YAP/TAZ in the biophysically similar condition nephrogenic systemic fibrosis and suggests a role of YAP/TAZ cytoplasmic sequestration in programmed cell death protein 1-ligand antagonist-induced scleroderma.
