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Review
. 2021 Mar 21;22(6):3203.
doi: 10.3390/ijms22063203.

SMADS-Mediate Molecular Mechanisms in Sjögren's Syndrome

Margherita Sisto  1 , Domenico Ribatti  1 , Sabrina Lisi  1
Affiliations
Review

SMADS-Mediate Molecular Mechanisms in Sjögren's Syndrome

Margherita Sisto et al. Int J Mol Sci. .

Abstract

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of _target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren's syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic _target for pSS.

Keywords: SMAD; Sjögren’s syndrome; TGF-β; epithelial-mesenchymal transition; fibrosis; inflammation.

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Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
TGF-β signalling is triggered through BMP or TGF-β ligands. Ligands bind the TGF-β receptor II (TGF-βR-II) which recruits and phosphorylates TGF-β receptor I (TGF-βR-I). In the TGF-β signalling pathway, TGF-βR-I phosphorylates the SMAD2 and 3, or SMAD1, 5, and 8. The cofactor SMAD4 forms a heterotrimeric complex with SMAD2/3 and SMAD1/5/8. Activated SMAD complex, translocate into the nucleus interacting with transcription factors and modulating or repressing the gene transcription. Feedback regulation is mediated by inhibitory SMAD 6/7. Both SMAD6 and SMAD7 are in turn induced by TGF-β receptors and regulated through the help of SMAD ubiquitination regulatory factors (Smurfs) 1 and 2.
Figure 2
Figure 2
Schematic illustration of canonical and non-canonical TGF-β signalling pathways. Canonical SMAD-dependent TGF-β signalling is initiated by TGF-β ligand binding to receptors TGFBRI/RII, which once activated, lead to the phosphorylation and activation of SMAD2/3 which, in turn, binds to cofactor SMAD4. The trimeric SMAD complex translocate into the nucleus, where they interact with other transcription factors to regulate _target gene expression. In the SMAD-independent pathways, the TGF-β receptor complex transmits its signal through other factors, such as RAS-RAF-MEK-ERK. Once activated, ERK1 and ERK2 can facilitate EMT by increasing the expression of EMT transcription factors. Moreover, activated TAK1/JNK/JUN factors act to regulate cellular apoptosis and proliferation, whereas they can also mediate metastasis, angiogenesis and cellular growth through other transcription factors.
Figure 3
Figure 3
Hypothetical scheme illustrating TGF-β/EMT signalling in SS. TGF-β activates both the canonical SMAD2/3 pathway and the non-canonical MAPK pathway, triggering the EMT process. An inflammatory microenvironment including proinflammatory cytokines such as IL-17, IL-22, and IL-6 may induce EMT through the TGF-β/SMAD and non-SMAD signalling pathways. The activation of transcription factors such as Snail, promotes the prolonged activation of EMT, repressing epithelial marker genes, as E-Cadherin, and activating genes regulating the mesenchymal phenotype, as Vimentin and Collagen Type 1. The epithelial cells trans-differentiated in myofibroblasts are responsible for progressive SG fibrosis. Alternatively, TGF-β can trigger the signals via non-SMAD pathways, such as the MAPK signalling cascade including phosphorylated ERK1/2, that ultimately lead to the activation of the EMT-dependent fibrosis program. An alternative hypothetical mechanism was also showed mediated by IFN-γ that, through the Jak1/Stat1 activation, causes the SMAD7-mediated inhibition of TGF-β signalling.
Figure 4
Figure 4
Modulation of the TGF-β signalling pathway by miRNAs. In response to TGF-β signal, the expression of a cohort of miRNAs is modulated. Several miRNAs are involved in the process of EMT-dependent tissue fibrosis by _targeting components of the TGF-β signalling pathway.
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