E3 Ligase Trim21 Ubiquitylates and Stabilizes Keratin 17 to Induce STAT3 Activation in Psoriasis

Yang, Luting; Jin, Liang; Ke, Yao; Fan, Xueli; Zhang, Tongmei; Zhang, Chen; Bian, Huijie; Wang, Gang

doi:10.1016/j.jid.2018.05.016

Cited by 71 publications

(47 citation statements)

References 45 publications

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“…TRIM21, which belongs to the TRIM family, is an E3 ubiquitin ligase with a RING domain. TRIM21 is widely involved in cell proliferation, differentiation, autophagy, innate immunity and migration [50][51][52][53]. Our previous mass spectrometry identified several E3 ligases include CHIP and TRIM21 as interacting proteins of PRMT5 in prostate cancer cells [11].…”

Section: Discussionmentioning

confidence: 94%

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

Tong

et al. 2020

Aging

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Osteosarcoma (OS) is the most common bone malignancy in adolescents and has poor clinical outcomes. Protein arginine methyltransferase 5 (PRMT5) has recently been shown to be aberrantly expressed in various cancers, yet its role in OS remains elusive. Here, we found that PRMT5 was overexpressed in OS and its overexpression predicted poor clinical outcomes. PRMT5 knockdown significantly triggered pronounced senescence in OS cells, as evidenced by the increase in senescence-associated β-galactosidase (SA-β-gal)-stained cells, induction of p21 expression, and upregulation of senescence-associated secretory phenotype (SASP) gene expression. In addition, we found that PRMT5 plays a key role in regulating DNA damaging agents-induced OS cell senescence, possibly, via affecting the repair of DNA damage. Furthermore, we found that TXNIP acts as a key factor mediating PRMT5 depletion-induced DNA damage and cellular senescence. Mechanistically, TRIM21, which interacts with PRMT5, was essential for the regulation of TXNIP/p21 expression. In summary, we propose a model in which PRMT5, by interaction with TRIM21, plays a key role in regulating the TXNIP/p21 axis during senescence in OS cells. The present findings suggest that PRMT5 overexpression in OS cells might confer resistance to chemotherapy and that targeting the PRMT5/TRIM21/TXNIP signaling may enhance the therapeutic efficacy in OS.

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Section: Discussionmentioning

confidence: 94%

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

Tong

et al. 2020

Aging

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“…Mass spectrometry identified E3‐ligase Trim21 in K17 ubiquitination, which promoted the stability of K17 in psoriatic keratinocytes via K63‐linked ubiquitination. The Trim21‐induced ubiquitination of K17 interacted with STAT3, promoting its activation and cell proliferation in psoriasis keratinocytes (Figure B) . This opens a new avenue for targeting ubiquitination in the potential treatment of psoriasis.…”

Section: Regulation Of K17mentioning

confidence: 87%

Keratin 17 in disease pathogenesis: from cancer to dermatoses

Yang

Zhang

Wang

2018

The Journal of Pathology

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Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue‐specific diseases, represented by steatocystoma multiplex and pachyonychia congenita. In this review, we summarize our findings concerning the regulatory mechanisms of K17 overexpression in psoriasis and compare them to the literature relating to other diseases. We discuss data that proinflammatory cytokines, including interleukin‐17 (IL‐17), IL‐22, interferon‐gamma (IFN‐γ), transforming growth factor‐beta (TGF‐β) and transcription factors glioma‐associated oncogene homolog 1/2 (Gli1/2), Nrf2 and p53 can regulate K17 by transcriptional and translational control. Moreover, post‐translational modification, including phosphorylation and ubiquitination, is involved in the regulation of K17 stability and biological functions. We therefore review the current understanding of the K17 regulatory mechanism and its pathogenic role in diseases from dermatoses to cancer. Prospects for anti‐K17 therapy in diagnosis, prognosis and disease treatment are also discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Keratin 17 (K17) is a marker of psoriasis that is undetectable in normal epidermis but markedly upregulated in psoriatic lesions ( 11 , 12 ). A recent study has suggested that IL-17 induces K17 in the epidermis by promoting the nuclear translocation of STAT3, which contributes to the pathogenesis of psoriasis ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

Lan

Wang

et al. 2020

Mol Med Rep

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Psoriasis is a chronic inflammatory skin disease characterized by well-defined scaly papules and plaques. Interleukin (IL)-17 is involved in its pathogenesis and promotes the proliferation of epidermal keratinocytes through signal transducer and activator of transcription 3 (STAT3) activation. Shikonin, a natural naphthoquinone isolated from Lithospermum erythrorhizon , possesses anti-inflammatory and immunosuppressive properties and can suppress IL-17-induced vascular endothelial growth factor expression by inhibiting the JAK/STAT3 pathway. In the present study, MTS, iCELLigence and RT-qPCR were used to determine the optimal concentration and duration of IL-17 or shikonin acting on HaCaT cells. The changes in the expression levels of genes associated with the IL-6/STAT3 pathway in differentially treated cells were analyzed via RT 2 Profiler™ PCR Array. Small interfering RNA was used to silence the expression levels of the target gene CCAAT/enhancer-binding protein δ (CEBPD). Western blotting and immunohistochemistry were used to evaluate the effect of shikonin on imiquimod-induced psoriasis in mice and the expression levels of CEBPD. Shikonin reversed IL-17-mediated downregulation of the tumor suppressor CEBPD in HaCaT cells. Moreover, low levels of CEBPD in the imiquimod-induced mouse model of psoriasis were restored by shikonin treatment, which ameliorated excessive keratinocyte proliferation. Taken together, these findings suggest that CEBPD plays a key role in the pathogenesis of psoriasis and can be targeted by shikonin as a potential therapeutic strategy.

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E3 Ligase Trim21 Ubiquitylates and Stabilizes Keratin 17 to Induce STAT3 Activation in Psoriasis

Cited by 71 publications

References 45 publications

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

Keratin 17 in disease pathogenesis: from cancer to dermatoses

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

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