The extracellular matrix glycoprotein fibrillin-1 in health and disease

Abstract

Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.

Keywords: FBN1; TGF-β; chronic kidney diseases; extracellular matrix; marfan syndrome.

FIGURE 1

The domain structure of FBN1 and the sites responsible for interacting with other proteins. LTBP, latent TGF-β-binding protein; cbEGF, calcium binding EGF; EGF-like, epidermal growth factor-like; 2C, 2-cysteine; BMP-2, bone morphogenetic protein 2; GDF-5, growth differentiation factor 5.

FIGURE 2

FBN1 mRNA expression in human tissues. (A) Human tissue and cell gene expression data were extracted from the online database https://www.gtexportal.org (dataset ENSG00000166147.13). The Y-axis represents the normalized expression values. (B) Immunohistochemical staining for FBN1. Renal expression and localization of FBN1 protein in various groups are depicted on representative micrographs. Control, nontumor kidney part obtained from individuals diagnosed with renal cell carcinoma; MN, membranous nephritis. Scale bar: 50 μm. Arrow indicates positive staining. (C) RNA-seq analysis shows the expression level (FPKM) of mouse FBN1 in normal (sham) and obstructed kidneys after unilateral ureteral obstruction (UUO). ^* p < 0.05. FPKM, fragments per kilobase per million mapped reads. Date are available at NCBI with accession number PRJNA846588.

FIGURE 3

FBN1 paradoxically promotes TGF-β activation in different settings. (A) In various pathological conditions, FBN1 is induced, which leads to TGF-β1 activation through integrin signaling. Activate TGF-β then activates Smad signaling through membranous TGFBRs. (B) In the setting of genetic diseases, alterations in FBN1 gene result in the loss-of-function of FBN1, which liberates TGF-β release. Activated TGF-β promotes Smad-mediated gene expression. TGFBR, TGF-β receptor.

FIGURE 4

The fate of peritubular endothelial cells is controlled by the tubule-derived FBN1 in chronic kidney disease (CKD). Diagram shows that injured tubular cells produce and secrete FBN1, which orchestrates the formation of a hostile FBN1-enriched microenvironment for endothelial cells. FBN1 then triggers endothelial cell apoptosis by a cascade of integrins/TGF-β1/Smad3 signaling.