Geranylgeranyl Pyrophosphate Promotes Profibrotic Factors and Collagen-Specific Chaperone HSP47 in Fibroblasts. J Cell Mol Med 2024 Dec;28(24):e70273
Date
12/24/2024Pubmed ID
39716037Pubmed Central ID
PMC11666423DOI
10.1111/jcmm.70273Scopus ID
2-s2.0-85212828748 (requires institutional sign-in at Scopus site)Abstract
Fibrosis, characterised by excessive extracellular matrix deposition, contributes to both organ failure and significant mortality worldwide. Whereas fibroblasts are activated into myofibroblasts, marked by phenotypic factors such as α-smooth muscle actin (α-SMA), periostin, fibroblast activation protein (FAP) and heat shock protein 47 (HSP47), the cellular processes of trans-differentiation for fibrosis development remain poorly understood. Herein, we hypothesised that the molecular signalling of geranylgeranyl pyrophosphate (GGPP), a crucial biochemical molecule for protein prenylation, is essential in the regulation of profibrotic mechanisms for fibroblast-to-myofibroblast activation. To test this hypothesis, we demonstrated pharmacological inhibition of geranylgeranyl pyrophosphate synthase (GGPS1) significantly decreased TGF-β1-dependent myofibroblast differentiation assessed by reduced α-SMA, periostin, FAP and HSP47 expression. Exogenous GGPP in the presence of GGPS1 inhibition restored TGF-β1-induced differentiation, supporting posttranslational requirements of GGPP modification during myofibroblast differentiation. Selective inhibition of either geranylgeranyl transferase or farnesyl transferase significantly impacted TGF-β1-induced myofibroblast α-SMA and HSP47 expression. The importance of protein prenylation as a key regulator of myofibroblast differentiation was remarkably revealed by an unexpected decrease in HSP47 expression. In contrast, direct HSP47 inhibition not only suppressed TGF-β1-induced α-SMA expression but surprisingly could not be rescued using exogenous GGPP. A selective role for the ER-resident chaperone HSP47 expression downstream of GGPP was suggested when the effects of GGPS1 inhibition on periostin expression were counteracted by GGPP and geranylgeranyl transferase inhibition. Taken together, our findings underscore for the first time the functional role of cholesterol synthesis-independent GGPP-dependent pathway in fibroblast-to-myofibroblast transition and open new potential therapeutic targets for antifibrosis therapies.
Author List
Ross GR, Vodanovic-Jankovic S, Benjamin IJAuthors
Ivor J. Benjamin MD Professor in the Medicine department at Medical College of WisconsinGracious R. Ross Research Scientist II in the Cardiovascular Center department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ActinsAlkyl and Aryl Transferases
Animals
Cell Adhesion Molecules
Cell Differentiation
Collagen
Fibroblasts
Fibrosis
HSP47 Heat-Shock Proteins
Humans
Myofibroblasts
Polyisoprenyl Phosphates
Signal Transduction
Transforming Growth Factor beta1
