Abstract
Fibrosis is an abnormal healing process that only repairs the structure of an organ after injury and does not address damaged functions. The pathogenesis of fibrosis is multifactorial and highly complex; numerous signalling pathways are involved in this process, with the transforming growth factor-β (TGF-β) signalling pathway playing a central role. TGF-β regulates the generation of myofibroblasts and the epithelial-mesenchymal transition by regulating transcription and translation of downstream genes and precisely regulating fibrogenesis. The TGF-β signalling pathway can be modulated by various post-translational modifications, of which SUMOylation has been shown to play a key role. In this review, we focus on the function of SUMOylation in canonical and non-canonical TGF-β signalling and its role in fibrosis, providing promising therapeutic strategies for fibrosis.
Highlights
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a wide range of biological processes, such as proliferation, differentiation, migration and metabolism [1]
We summarize the role of SUMOylation in Smad and non-Smad TGF-β signalling pathways and propose that SUMOylation is important in TGF-β-mediated biological processes
Most studies to date on the effect of SUMO modification on TGF-β pathway activity have focused on cancer
Summary
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a wide range of biological processes, such as proliferation, differentiation, migration and metabolism [1]. The TGF-β ligand first binds and activates the TGF-β type II receptor (TβRII), which in turn recruits and phosphorylates TGF-β type I receptor (TβRI) [1]. The complex associates with other transcription factors to positively or negatively regulate the transcription of target genes [3]. I-Smads act as inhibitors by recruiting the E3 ubiquitin ligase Smad ubiquitination regulatory factor 2 (Smurf2) to degrade activated TβRI via ubiquitination [5]. SUMOylation modulates signal transduction by altering the subcellular localization, protein–DNA binding and ubiquitin-dependent degradation of target substrates [9]. The SUMOE3 ligase recognizes substrates and promotes transfer of the SUMO protein from Ubc to the target protein [14]. SUMOylation is a completely reversible enzymatic reaction, and SUMO proteins can be removed from target proteins by SUMO-specific proteases (SENPs) [16]. Seven SENPs (SENP1–3 and SENP5–8) have been identified [17], and SENP family members can reverse the modification and cause maturation of pro-SUMO to conjugatable SUMO via a modification [18]
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