Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a variety of human disorders, such as inflammatory diseases and cancers. Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases. Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability, receptor internalization, enzyme activity, and protein-protein interactions. Ubiquitination is tightly regulated by ubiquitin E3 ligases and can be reversed by deubiquitinating enzymes. Recent studies have been focusing on investigating the effect of protein stability in the regulation of cell-cell junctions. Ubiquitination and degradation of cadherins, claudins, and their interacting proteins are implicated in epithelial and endothelial barrier disruption. Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases’ biological activities. Taken together these studies, ubiquitination plays a critical role in modulating cell junctions and motility. In this review, we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions, including junction proteins, their interacting proteins, and small Rho GTPases. We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiquitination on human disorders caused by dysfunction of cell junctions.

Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.

Indole‐3‐acetic acid (IAA) is recognized as a common plant growth hormone. It is also detectable in mammals, as it can be produced by gut microbiota in the gut. Current research works have shown that IAA is a multifaceted compound with significant consequences for several physiological and pathological processes. Higher levels of IAA occur in chronic kidney disease because decreased renal clearance contributes to cardiovascular and liver dysfunction. In contrast, IAA demonstrates protective effects by modulating oxidative stress, inflammation, and lipid metabolism in nonalcoholic fatty liver disease. IAA also shows potential therapeutic benefits in lung disorders such as acute lung injury, pulmonary fibrosis, and chronic obstructive pulmonary disease. Furthermore, IAA shows potential as an adjunct in cancer therapy, where it synergizes with chemotherapy regimens by endorsing oxidative stress and autophagy. Beyond cancer‐related applications and metabolic disorders, IAA's role in neuroinflammation, mainly in conditions such as sepsis‐associated encephalopathy and depression, underscores its potential as a therapeutic agent targeting the gut–brain axis. Furthermore, IAA is a potent oral hypoglycemic agent with mitigating effects on metabolic disorders associated with obesity and diabetes. This review provides an overview of the diverse roles of IAA in disease pathophysiology, its therapeutic promise, and the need for further research to better understand its mechanistic pathways. Understanding these complex effects could pave the way for novel microbiota‐based therapies to address a range of chronic diseases and improve patient outcomes.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is associated with aberrant activation of TGF-β, myofibroblast differentiation, and abnormal extracellular matrix (ECM) production. Proper regulation of protein stability is important for maintenance of intracellular protein homeostasis and signaling. Ubiquitin E3 ligases mediate protein ubiquitination, and deubiquitinating enzymes (DUBs) reverse the process. The role of ubiquitin E3 ligases and DUBs in the pathogenesis of IPF is relatively unexplored. In this review, we provide an overview of how ubiquitin E3 ligases and DUBs modulate pulmonary fibrosis through regulation of both TGF-β–dependent and –independent pathways. We also summarize currently available small-molecule inhibitors of ubiquitin E3 ligases and DUBs as potential therapeutic strategies for the treatment of IPF.