USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

An, Ran; Wang, Peng; Guo, Hao; Liuyu, Tianzi; Zhong, Bo; Zhang, Zhi-Dong

doi:10.1016/j.cellin.2022.100047

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…Although additional studies are required to assess the safety of modulating the ACE2 system, results from studies in mice lacking the Ace2 gene have shown that these animals are healthy, fertile, and exhibit no abnormal cardiac characteristics ( 56 ). Moreover, mice with Usp2 deficiency are able to survive ( 57 , 58 ), and our in vivo studies have revealed that there is no substantial change in angiotensin-(1–7) concentrations after a short period of treatment with ML364 (fig. S8B).…”

Section: Discussionmentioning

confidence: 83%

“…The study was approved by the Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committee (IACUC; protocol number 019-2021) and performed in accordance with guidelines established by the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Usp2 -null mice have a C57BL/6 background, as described previously ( 57 , 58 ). For the in vivo SARS-CoV-2 challenge study, K18-hACE2 transgenic mice (strain no.…”

Section: Methodsmentioning

confidence: 99%

“…established by the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Usp2-null mice have a C57BL/6 background, as described previously (57,58). For the in vivo SARS-CoV-2 challenge study, K18-hACE2 transgenic mice (strain no.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

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USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

Dang,

Bai,

Dong

et al. 2023

Sci. Transl. Med.

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Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2.

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Section: Discussionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

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USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

Dang,

Bai,

Dong

et al. 2023

Sci. Transl. Med.

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“…This results in deposition of collagen and fibronectin to promote intestinal fibrosis ( Liu et al, 2021 ). Other recent work has suggested that ubiquitin-specific protease 2 (USP2), which is upregulated in intestinal myeloid cells during IBD and mouse models of colitis, increases the expression of collagen and alpha smooth muscle actin (αSMA), leading to further ECM remodeling and tissue stiffening ( An et al, 2022 ). Collagen-I deposition in the intestine also activates the YAP/TAZ pathway in epithelial cells through Fak/Src signaling to initiate a regenerative cascade to induce a fetal-like state in the colonic epithelium, where cells become more motile and prone to reorganization compared to homeostatic conditions ( Yui et al, 2018 ).…”

Section: Mechanosensing Feedback Loops In Chronic Inflammatory Diseasesmentioning

confidence: 99%

Mechanosensory feedback loops during chronic inflammation

Saha

Müller

Clark

2023

Front. Cell Dev. Biol.

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Epithelial tissues are crucial to maintaining healthy organization and compartmentalization in various organs and act as a first line of defense against infection in barrier organs such as the skin, lungs and intestine. Disruption or injury to these barriers can lead to infiltration of resident or foreign microbes, initiating local inflammation. One often overlooked aspect of this response is local changes in tissue mechanics during inflammation. In this mini-review, we summarize known molecular mechanisms linking disruption of epithelial barrier function to mechanical changes in epithelial tissues. We consider direct mechanisms, such as changes in the secretion of extracellular matrix (ECM)-modulating enzymes by immune cells as well as indirect mechanisms including local activation of fibroblasts. We discuss how these mechanical changes can modulate local immune cell activity and inflammation and perturb epithelial homeostasis, further dysregulating epithelial barrier function. We propose that this two-way relationship between loss of barrier function and altered tissue mechanics can lead to a positive feedback loop that further perpetuates inflammation. We discuss this cycle in the context of several chronic inflammatory diseases, including inflammatory bowel disease (IBD), liver disease and cancer, and we present the modulation of tissue mechanics as a new framework for combating chronic inflammation.

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USP2 Promotes the Proliferation and Inflammation of Fibroblast-Like Synovial Cells in Rheumatoid Arthritis Through Deubiquitination of TRAF2

Liu,

Zhang,

Liu

et al. 2024

Biochem Genet

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USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

Cited by 7 publications

References 60 publications

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

Mechanosensory feedback loops during chronic inflammation

USP2 Promotes the Proliferation and Inflammation of Fibroblast-Like Synovial Cells in Rheumatoid Arthritis Through Deubiquitination of TRAF2

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