Preventive Effect of Pharmaceutical Phytochemicals Targeting the Src Family of Protein Tyrosine Kinases and Aryl Hydrocarbon Receptor on Environmental Stress-Induced Skin Disease

Paik, So Jeong; Kim, Dong Joon; Jung, Sung Keun

doi:10.3390/ijms24065953

Cited by 3 publications

(6 citation statements)

References 118 publications

(179 reference statements)

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“…We have also demonstrated that Src kinase plays a critical role in ALTOinduced TBK1 phosphorylation and downstream signaling (Fig 4). In the human skin, activated Src is involved in regulating cell adhesion, migration, and proliferation in processes such as wound healing and skin regeneration [49,50].…”

Section: Discussionmentioning

confidence: 99%

“…The pTRIPZ-STING R284S construct was generated in our previous studies [36]. The viral gene constructs used in this study were sourced as follows: pGwf and phGf were from Addgene; pALTOw, pMtw (ST), pWm (VP1), pMono-Zeo, pMono-ADL (LT) and ph2m (VP2) were from the Christopher Buck Laboratory; and the pcDNA4c-57kT construct was generated by first fusing the full 57kT ORF using two-step PCR from pcDNA4c-LT1-817 [51] and then cloning it into the pcDNA4c backbone using the KpnI and XhoI restriction sites.…”

Section: Methodsmentioning

confidence: 99%

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Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

Wang,

Senay,

Luo

et al. 2024

Preprint

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While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative-feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

Wang,

Senay,

Luo

et al. 2024

Preprint

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“…AhR-modulating drugs can reduce macrophage activation and inflammation in rosacea by targeting the skin’s response to environmental toxins ( 69 ). Tapinarof, an innovative topical treatment acting as an AhR agonist, holds promise in treating rosacea ( 70 ). This molecular mechanism focuses on the AhR, a ligand-activated transcription factor located in the cytoplasm ( 71 ).…”

Section: Progress and Challenges In Macrophage-targeted Therapies For...mentioning

confidence: 99%

“…This molecular mechanism focuses on the AhR, a ligand-activated transcription factor located in the cytoplasm ( 71 ). When tapinarof binds to AhR, it activates the receptor, leading to its translocation into the nucleus of skin cells ( 70 , 72 ). This triggers the transcription of target genes that regulate inflammatory responses and strengthen the skin barrier function ( 73 ).…”

Section: Progress and Challenges In Macrophage-targeted Therapies For...mentioning

confidence: 99%

“…Tapinarof has the potential to alleviate inflammatory responses and vascular dysregulation in rosacea ( 74 , 75 ). Tapinarof’s potential effectiveness in improving skin barrier integrity may help alleviate rosacea symptoms ( 70 , 76 , 77 ). Referring to current sources is recommended for the latest information, as it may have evolved.…”

Section: Progress and Challenges In Macrophage-targeted Therapies For...mentioning

confidence: 99%

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The role of macrophages in rosacea: implications for targeted therapies

Liu,

Zhou,

Chu

et al. 2023

Front. Immunol.

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IntroductionRosacea, a widespread chronic skin condition, may be influenced by macrophages, key immune cells in the skin, although their exact role is not yet fully understood. This review delves into the function of macrophages, their potential contribution to rosacea pathogenesis, current treatments, and promising macrophage-targeted therapies. It concludes by identifying knowledge gaps and potential areas for future rosacea research.MethodLeveraging systematic and narrative literature review techniques, we conducted a comprehensive search of databases such as PubMed, Embase, and Web of Science. Utilizing keywords like “rosacea” and “macrophages”, we targeted English articles from the last 5 years (2018-2023). We manually checked reference lists of relevant articles for additional studies. We included only articles emphasizing macrophages’ role in rosacea and/or the development of related therapies and published within the specified timeframe.ResultsThe systematic search of electronic databases yielded a total of 4,263 articles. After applying the inclusion and exclusion criteria, 156 articles were selected for inclusion in this review. These articles included original research studies, review articles, and clinical trials that focused on the role of macrophages in rosacea and/or the development of macrophage-targeted therapies for the disease. The selected articles provided a comprehensive and up-to-date overview of the current state of research on macrophages in rosacea, including their function in the skin, the potential mechanisms through which they may contribute to rosacea pathogenesis, and the current treatments and therapies available for the disease. Additionally, the articles identified gaps in knowledge regarding the role of macrophages in rosacea and suggested potential areas for future research.ConclusionThis literature review emphasizes the important role that macrophages, vital immune cells in the skin, may play in the pathogenesis of rosacea, a common chronic inflammatory skin disorder. The selected studies suggest potential mechanisms by which these cells might contribute to rosacea progression, although these mechanisms are not yet fully understood. The studies also spotlight current rosacea treatments and illuminate the promising potential of new macrophage-focused therapies. Despite these insights, significant gaps persist in our understanding of the precise role of macrophages in rosacea. Future research in this area could provide further insights into the pathogenesis of rosacea and contribute to the development of more effective, targeted therapeutic strategies.

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Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

Wang,

Senay,

Luo

et al. 2024

PLoS Pathog

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While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.

show abstract

Preventive Effect of Pharmaceutical Phytochemicals Targeting the Src Family of Protein Tyrosine Kinases and Aryl Hydrocarbon Receptor on Environmental Stress-Induced Skin Disease

Cited by 3 publications

References 118 publications

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

The role of macrophages in rosacea: implications for targeted therapies

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

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