Abstract
The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor-β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1-induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1-mTORC1-ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer.
Highlights
Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases [1]
Expression of the serine-glycine biosynthetic pathway genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), phosphoserine phosphatase (PSPH) and serine hydroxymethyltransferase (SHMT) 2 were all increased following transforming growth factor-β1 (TGF-β1) treatment. This increase was inhibited by AZD8055 treatment, whereas rapamycin had no effect (Fig. 1C), indicating that rapamycin-insensitive mechanistic target of rapamycin (mTOR) signaling may play a critical role in enhancing the expression of genes involved in serine and glycine biosynthesis in response to TGF-β1 stimulation
We report a critical role for this axis, acting in cooperation with Smad3 to promote the production of activating transcription factor 4 (ATF4) which in turn orchestrates the subsequent transcriptional amplification of the glucose-derived serineglycine biosynthetic pathway (Fig. 8)
Summary
Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases [1]. Despite the rising incidence of fibrotic disease and intense research efforts, there remains a paucity of effective treatment options. Idiopathic pulmonary fibrosis (IPF) represents the most rapidly progressive and lethal of all fibrotic diseases and is associated with a dismal median survival of 3 years from diagnosis [2, 3]. The approval of pirfenidone and the small molecule tyrosine kinase inhibitor, nintedanib, for the treatment of IPF represented a watershed moment for the development of anti-fibrotic therapeutics, these agents slow but do not halt disease progression [4, 5]. There remains a pressing need to identify novel anti-fibrotic therapeutic strategies [6]
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