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Table 5 Selected genes in the consensus lung network

From: A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

Functional module

Gene symbol

Description

Network position

Up in

Function/potential role in disease

Cell cycle

BUB3

BUB3 mitotic checkpoint protein

-

Early SSc-PF/NSIP

Encodes a mitotic cell cycle checkpoint protein that regulates the onset of anaphase

CDC7

Cell division cycle 7

-

-

Regulates MCM complex

MCM3

Minichromosome maintenance complex component 3

-

Early SSc-PF/NSIP

Subunit of minichromosome maintenance (MCM) complex

MSH6

MutS homolog 6

-

Early SSc-PF/NSIP

Participates in DNA mismatch repair.

ECM disassembly/wound healing

CD44

CD44 molecule (Indian blood group)

Bridge

-

A hyaluronic acid receptor that can interact with many other ligands found in the ECM. Primary idiopathic PF fibroblasts exhibit an invasive phenotype that was abrogated with treatment with anti-CD44 [39]

CD63

CD63 molecule

-

-

Has been observed to interact with TIMP1 [83]

CTSB

Cathepsin B

-

-

Regulates NPC2 secretion, TNF-alpha production, and cholesterol trafficking genes in an animal model of obesity [51]

CTSL

Cathepsin L

-

-

Regulates NPC2 secretion, TNF-alpha production, and cholesterol trafficking genes in an animal model of obesity [51]

GLB1

Galactosidase, beta 1

-

Early SSc-PF/NSIP

Mutations in this gene can lead to GM1-gangliosidosis, a manifestation of which includes foam cell accumulation in the lungs [84]

NPC2

Niemann-Pick disease, type C2

Hub

Early SSc-PF/NSIP

Mutations in this gene result in a lipid storage disorder. Functions in the regulation of cholesterol trafficking through the lysosome by binding to cholesterol released from low density lipoproteins taken up by cells

TGFBI

Transforming growth factor, beta-induced

Bridge

Late SSc-PF/UIP

Induced by phagocytosis of apoptotic debris in monocyte-derived MØs and regulates collagen turnover [44]

TIMP1

TIMP metallopeptidase inhibitor 1

-

Early SSc-PF/NSIP

Has been observed to interact with CD63 and overexpression has been noted to inhibit apoptosis in a CD63-dependent manner [83]

Innate immune response/NFkB signaling/apoptotic process

BIRC3

Baculoviral IAP repeat-containing protein 3

-

Late SSc-PF/UIP

Has antiapoptotic activity through interactions with caspases as well as the TNF superfamily members TRAF1 and TRAF2 [85, 86]

CYR61

Cysteine-rich, angiogenic inducer, 61

 

Late SSc-PF/UIP

Also known as CCN1. Implicated in apoptosis in fibroblasts [87]. Has been shown to play a role in Fas-mediated and TRAIL-induced apoptosis [88, 89]

DUSP6

Dual specificity phosphatase 6

-

Late SSc-PF/UIP

Plays a role in the positive regulation of apoptosis [90]

FAS

Fas cell surface death receptor

-

Early SSc-PF/NSIP

Cell surface death receptor

NFKBIE

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon

-

-

Negative regulator of NFkB signaling

PLAUR

Plasminogen activator, urokinase receptor

Bridge

Late SSc-PF/UIP

Also known as uPAR. Contains an SSc risk SNP. Pulmonary fibroblasts from patients with idiopathic PF over express uPAR and that uPAR ligation results in a hypermotile phenotype [40]

PLSCR1

Phospholipid scramblase 1

-

-

Regulates phospholipid membrane asymmetry

TNFAIP3

Tumor necrosis factor, alpha-induced protein 3

Hub

 

Also known as A20. Contains an SSc risk SNP (also associated with other autoimmune conditions). Negative regulator of NFkB signaling

TNFSF10

Tumor necrosis factor (ligand) superfamily, member 10

Bridge

-

Also known as TRAIL. Elevated in serum of SSc patients [91]

TNFRSF10B

Tumor necrosis factor receptor superfamily, member 10b

-

Late SSc-PF/UIP

Also known as TRAILR2

IFN/antigen presentation

HLA-E

Major histocompatibility complex, class I, E

-

-

Class I MHC molecule

HLA-F

Major histocompatibility complex, class I, F

-

-

Class I MHC molecule

IFITM1

IFN induced transmembrane protein 1

-

SSc-PF (UIP and NSIP)

IFN signaling

IFITM2

IFN induced transmembrane protein 2

-

Early SSc-PF/NSIP

IFN signaling

IFITM3

IFN induced transmembrane protein 3

-

Early SSc-PF/NSIP

IFN signaling

IRF1

IFN regulatory factor 1

-

Late SSc-PF/UIP

Activator of type I IFN signaling

OAS1

2′-5′-Oligoadenylate synthetase 1, 40/46 kDa

-

Early SSc-PF/NSIP

Involved in innate immune response to viral infection

Response to TGF-beta

CAV1

Caveolin 1

-

-

Contains an SSc risk SNP

CTGF

Connective tissue growth factor

-

-

Also known as CCN2. Has been shown to play a role in Fas-mediated and TRAIL-induced apoptosis [88, 89]

DAB2

Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila)

-

SSc-PF (UIP and NSIP)

Required for the epithelial to mesenchymal transition induced by TGF-beta in mouse and for type II TGFbR recycling [92, 93]

FN1

Fibronectin 1

-

-

Extracellular matrix protein.

LAMC1

Laminin gamma1 chain

Hub

Early SSc-PF/NSIP

Expression of this gene is essential for the development of basement membranes [94]

THBS1

Thrombospondin 1

-

-

Mediates cell-to-cell and cell-to-matrix interactions. Putative biomarker of modified Rodnan skin score [95]