Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

WWP2 Regulates Kidney Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts

Background: Renal fibrosis is a common pathological endpoint in CKD that is challenging to reverse, and myofibroblasts are responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM). Recent studies have unveiled myofibroblasts diversity in terms of proliferative and fibrotic characteristics, which are linked to different metabolic states. We previously demonstrated the regulation of ECM genes and tissue fibrosis by WWP2, a multifunctional E3 ubiquitin-protein ligase. Here, we investigate WWP2 in renal fibrosis and in the metabolic reprograming of myofibroblasts in CKD. Methods: We used kidney samples from CKD patients and WWP2 -null kidney disease mice models, and leveraged single cell RNA-seq analysis to detail the cell-specific regulation of WWP2 in fibrotic kidneys. Experiments in primary cultured myofibroblasts by bulk-RNA seq, ChIP-seq, metabolomics and cellular metabolism assays, were used to study the metabolic regulation of WWP2 and its downstream signaling. Results: The tubulointerstitial expression of WWP2 was associated with fibrotic progression in CKD patients and in murine kidney disease models. WWP2 deficiency promoted myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis in vivo . In renal myofibroblasts, WWP2 deficiency increased fatty acid oxidation and activated the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. WWP2 suppressed the transcription of PGC-1α, a metabolic mediator of fibrotic response, and pharmacological inhibition of PGC-1α partially abrogated the protective effects of WWP2 deficiency on myofibroblasts. Conclusions: WWP2 regulates the metabolic reprogramming of profibrotic myofibroblasts by a WWP2-PGC-1α axis, and WWP2 deficiency protects against kidney fibrosis in CKD

The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis

AbstractNon-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.</jats:p

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

AbstractCardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.</jats:p

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

An amendment to this paper has been published and can be accessed via a link at the top of the paper.</jats:p