Involved related pathological processes
Relationship between YAP/TAZ and inflammation
An appropriate inflammatory response is critical for the restoration of tissue homeostasis after injury or infection, but how this response is regulated by the physical properties of the cellular and tissue microenvironment is not fully understood [47]. Recently, multiple studies have revealed the role of YAP/TAZ in regulating inflammatory and immune responses [74]. YAP/TAZ are primary sensors of the cellular microenvironment, integrating cell polarity and mechanical signaling with growth factor signaling and inflammation [4]. YAP/TAZ-dependent function is associated with the termination of NF-κB-dependent transcription of inflammatory genes by inducing IκBa expression[75]. Deletion of YAP/TAZ increases the expression of inflammatory genes, resulting in elevated local inflammation and enhanced accumulation and persistence of inflammatory cells[76]. Activation of the downstream molecules of the Hippo pathway YAP/TAZ in hepatocytes can promote the expression of inflammatory (TNF, IL1β) proteins, thereby stimulating hepatic inflammation [77]. Additionally, increased nuclear expression of YAP/TAZ, a mediator of the Hippo pathway in lung epithelial type II cells, promotes AECII activity, whereas mice lacking YAP/TAZ exhibit prolonged pulmonary inflammatory responses during bacterial pneumonia and alveolar epithelial regeneration delay[76]. In the corneal epithelium, persistent inflammation causes ECM deposition and fibrosis, leading to activation of YAP/TAZ mechanotransduction [58]. In this process, NF-κB is considered to be one of the important targets of YAP/TAZ and plays an anti-inflammatory role in regulating innate immunity and autoimmunity [76,78,79]. Phosphorylated YAP is sufficient to reduce inflammation in osteoarthritis by inhibiting the NF-κB signaling pathway[78]. Overexpression of constitutively active TAZ significantly reduces the secretion of inflammatory cytokines caused by overactivation of the NF-κB pathway and Rictor siRNA transfection. The Rictor/mTORC2 signaling pathway inhibits inflammation by inhibiting YAP/TAZ degradation and YAP/TAZ nuclear translocation[74].
Relationship between YAP/TAZ and fibrosis
Recent studies have demonstrated aberrant activation of YAP/TAZ in fibrosis in both animal models and human tissues[66]. YAP/TAZ is activated in response to increased mechanical stress, such as when cells adopt a diffuse cell morphology, undergo adhesion to a hard ECM, or deform due to substrate topology. All of these conditions affect the structural organization of the F-actin cytoskeleton, thereby favoring localized adhesion and actin stress fiber formation [58]. In fibroblasts, ECM stiffness mechanically activates YAP/TAZ, promoting the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, which establishes a feedforward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ is activated by disruption of cell polarity and increased ECM stiffness in fibrotic tissue, thereby promoting epithelial cell proliferation and survival [80].
YAP/TAZ and tissue, organ regeneration and wound healing
YAP/TAZ has recently been shown to be a key mediator of wound healing and tissue regeneration in response to tissue damage[1]. During these processes, YAP/TAZ is activated by intracellular and external signals [2]. During skin wound healing, YAP/TAZ-mediated nuclear signaling is indispensable for TGF-β signaling [81]. Mechanistically, calcitriol promotes crosstalk between the YAP/TAZ and TGF-β/Smad signaling pathways, triggering EMT in keratinocytes during wound healing[82]. Extensive work has identified YAP/TAZ as key regulators of cell proliferation and ’stemness’, especially during organ growth and regeneration [83]. Exciting results have been observed in mice stimulating organ repair and regeneration in nonregenerative organs [84]. The mouse heart is currently the most prominent example of the beneficial regenerative effects of experimental activation of YAP/TAZ, but activation of YAP/TAZ also contributes to the regeneration of other organs in adult mice, including the liver [85], muscle, and gut[84,86]. These studies raise the possibility of manipulating YAP/TAZ downstream of the Hippo pathway in injured human organs as a means to stimulate regeneration of endogenous mechanisms. However, therapeutic activation of YAP/TAZ for regeneration may have significant risks, as its overactivation has been shown to promote cancer development [84].
Role in gut-related diseases
The role of YAP/TAZ in inflammatory bowel disease
Crohn’s disease is a major form of inflammatory bowel disease characterized by chronic inflammation, recurrent mucosal healing and deposition of extracellular matrix (ECM) in the mucosa and submucosa, leading to the development of structural fibrosis and intestinal obstruction[87]. YAP/TAZ expression is significantly upregulated in stenotic fibroblasts, which correlates with the YAP/TAZ target gene signature. Downregulation of YAP/TAZ genes inhibits intestinal fibroblast activation. In intestinal fibroblasts, YAP/TAZ is activated by the Rho-ROCK1 signaling pathway. The high expression of YAP/TAZ is positively correlated with the expression of ROCK1, which is a prognostic marker of intestinal obstruction in CD patients [66]. Meanwhile, the YAP/TAZ and TEAD1/2/4 genes are also transcriptionally regulated by the Wnt/β-catenin signaling pathway in the intestine, and the nuclear translocation of YAP/TAZ in tissue injury depends on the Src family kinase signaling pathway. Therefore, when Src family kinases inhibit LATS1/2, thereby driving YAP/TAZ to the nucleus, they activate YAP/TAZ-TEAD-mediated transcription, thereby promoting intestinal tissue regeneration [63]. The study also found that the IL-6 coreceptor gp130 is activated during intestinal inflammation, and the expression of a constitutively active form of gp130 is activated and requires YAP/TAZ to induce enterocyte proliferative responses and intestinal regeneration in a model of inflammatory colitis. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to inhibit intestinal fibrosis in CD[66].
The role of YAP/TAZ in intestinal cancer
YAP/TAZ are potent inducers of cell proliferation and, in many cases, important drivers of tumorigenesis [4,19,88]. Activation or overexpression of YAP/TAZ has been shown to lead to cellular transformation, tumor growth, metastasis and drug resistance[1,11]. Colorectal carcinogenesis typically begins with constitutive WNT signaling, resulting in nuclear accumulation of transcriptional coactivators, including YAP/TAZ. Thereafter, mutations and epigenetic events follow, inducing genetic programs that drive invasion and metastasis [89]. Consistently, TIAM1 was found to be part of a cytoplasmic destruction complex that regulates TAZ/YAP stability. It was further found that, in naive intestinal epithelial cells, when the destruction complex is inactivated, TIAM1 and TAZ/YAP aggregate and translocate from the cytoplasm to the nucleus. However, in the nucleus, TIAM1 continues to antagonize nuclear TAZ/YAP function despite the formation of WNT signaling, thereby inhibiting cell migration and invasion. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with bTrCP. Nuclear TIAM1 inhibits the interaction of TAZ/YAP with TEADs and suppresses the expression of TAZ/YAP target genes involved in epithelial-mesenchymal transition, cell migration and invasion, thereby inhibiting the migration and invasion of colorectal cancer cells [89]. The Hippo pathway in mammals can also inhibit the phosphorylation of YAP/TAZ by the large tumor suppressor (LATS) family of Hippo core kinases via interaction with 14-3-3 proteins and/or via the ubiquitin–proteasome pathway. Degradation leads to cytoplasmic septum to inhibit intestinal tumor development [15,90,91]. YAP and TAZ are downstream molecules of the Hippo pathway and are widely expressed in human tissues under normal physiological conditions. When the Hippo kinase module is repressed, YAP and TAZ lose their phosphorylation and translocate to the nucleus, inhibiting apoptosis and promoting EMT and tumor formation. YAP can also suppress the activity of the Hippo pathway by activating the PI3K/AKT pathway. The PI3K/AKT pathway is a critical transduction pathway involved in regulating cell proliferation, and enhancement of PI3K activity contributes to AKT activation and promotes the continued growth of tumor cells[92]. On the other hand, the transcriptional coactivators YAP/ TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. The epigenetic landscape of human CRC unveils the existence of an aberrant pan-cancer core of enhancers regulated by the transcriptional coactivators YAP/TAZ and active in more than 20 types of human malignancies[93].
Conclusion and prospects
YAP/TAZ acts as a homologous transcriptional coactivator and plays an important role in promoting cell proliferation, stem cell maintenance, and tissue homeostasis. In the inflammatory process, the deletion of YAP/TAZ can increase the expression of inflammatory genes, leading to an increase in local inflammation, the accumulation of inflammatory cells and an increase in persistence. Simultaneous activation or overexpression of YAP/TAZ has been shown to lead to cellular transformation and tumor development. The persistent inflammatory response, in turn, leads to abnormal activation of YAP/TAZ and promotes local adhesion and the formation of actin stress fibers, which subsequently leads to fibrosis. Overactivated YAP/TAZ can lead to cell proliferation, metastasis, and EMT. Therefore, YAP/TAZ play an important role in the process of intestinal disease. YAP/TAZ can regulate the development of inflammation and the formation of fibrosis in the later stages of intestinal inflammatory diseases. YAP/TAZ, which is overactivated in intestinal tumor diseases, promotes cell transformation, tumor growth, metastasis, and drug resistance. YAP/TAZ is a multifunctional transcriptional activator that is a downstream effector of the Hippo and Wnt pathways, plays a negative regulatory role, participates in a variety of cellular responses and is closely related to cell proliferation and metabolism. In addition, YAP/TAZ can act upstream of Notch signaling by activating Notch receptors. Therefore, this paper discusses the proteins related to YAP/TAZ binding, the related pathways involved, the related pathological processes, and their role in intestinal diseases. However, other relevant binding proteins and mechanisms of action of YAP/TAZ in the course of intestinal disease have yet to be discovered. We suspect that regulating the expression of YAP/TAZ by regulating YAP/TAZ-related proteins and pathways can improve the occurrence and development of intestinal diseases. As people pay increasing attention to the role of YAP/TAZ in disease, more regulatory mechanisms will be mined and make a major achievement. Next step, we will study the clinical application of YAP/TAZ in intestinal diseases and make the discovery of these mechanisms benefit patients.