Ubiquitination-proteasome system: A new player in the pathogenesis of psoriasis and clinical implications

Yang, Luting; Guo, Weinan; Zhang, Shaolong; Wang, Gang

doi:10.1016/j.jdermsci.2017.12.002

Cited by 30 publications

(15 citation statements)

References 76 publications

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“…Using siRNA technique, UCHL1 /PGP 9.5-expressing cell lines showed more than 200 downregulated and comparable number of upregulated genes engaged in most cellular processes, also those responsible for molecular background of psoriasis [ 50 ]. So, molecular mechanisms of protein ubiquitination seem to be deregulated in inflammatory-associated diseases and other ubiquitin-related enzymes participating in signaling pathways are analyzed to better explain their roles in psoriasis disease [ 51 ]. Furthermore, new findings connect neurodegenerative symptoms and neuropathic pain with activation of ubiquitination pathways; however, sensations, such as itch, are still poorly explained in that context [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Kupczyk

Reich

Gajda

et al. 2018

BioMed Research International

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Psoriasis is an immunogenetic skin disease manifesting as plaque lesions on the skin. Patients with psoriasis frequently suffer from itch, an unpleasant sensation causing a desire to scratch. Psoriatic itch is mainly transmitted by unmyelinated C-fibers; however, the exact molecular mechanism of psoriatic itch is still unexplained. Protein gene product 9.5 (PGP 9.5) is a panneurological marker commonly used for analysis of peripheral peptidergic and nonpeptidergic nerves and identification of cutaneous neuro-immune-endocrine cells. However, some studies suggested that nonneuronal cells, like keratinocytes, may also express PGP 9.5. This phenomenon might be linked with impaired axonal transport, keratinocyte injury, or dysfunctions of neuro-immune-cutaneous connections. The aim of this study was to analyze the expression of PGP 9.5 in psoriatic skin. We observed significantly altered density of PGP 9.5-positive axonal nerve terminals in pruritic lesional (p=0.04) and nonlesional psoriatic skin (p>0.001) compared with controls. In contrast, no significant differences were observed between psoriatic skin without itch and controls. Furthermore, PGP 9.5 expression by suprabasal keratinocytes (SBKs) was significantly increased in itchy skin lesions (p=0.007) compared to skin without itch, and a positive correlation was observed between PGP 9.5 expression and itch intensity (r=0.64; p=0.02). Our findings indicate changes in peripheral innervations and psoriatic keratinocytes, which may influence neuro-immune-cutaneous homeostasis and modulate itch transmission.

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Section: Discussionmentioning

confidence: 99%

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Kupczyk

Reich

Gajda

et al. 2018

BioMed Research International

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“…Ubiquitination is another key PTM that modulates protein stability and protein–protein interactions . Recently, our group delineated a mechanism in which K17 could be ubiquitylated in human keratinocytes.…”

Section: Regulation Of K17mentioning

confidence: 99%

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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“…For example, binding to K63-polyubiquitin chains would induce the conformational change and activation of TAB2 (Xia et al, 2009). More importantly, ubiquitination has been recognized as an important mechanism in the pathogenesis of autoimmune diseases including systemic lupus erythematosus, diabetes, and psoriasis (Ardestani et al, 2014;Goru et al, 2016;Guo et al, 2016;Liu et al, 2010;Yang et al, 2018). In psoriatic epidermis, tripartite motif-containing protein 32 (Trim32), an E3-ubiquitin ligase, was found to be overexpressed and able to induce psoriatic chemokine CCL20 secretion (Liu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Jin

et al. 2018

Journal of Investigative Dermatology

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Keratin 17 (K17), a marker of keratinocyte hyperproliferation, is a type I intermediate filament that is overexpressed in psoriatic epidermis and plays a critical pathogenic role by stimulating T cells. However, the posttranslational modification of K17, which is reversible and targetable, has not been elucidated. Herein, we reported that K17 could be modified through ubiquitination that controlled its stability and led to the phosphorylation and nuclear translocation of its interactor signal transducers and activators of transcription 3 (STAT3), which is a key regulator of cell proliferation in psoriasis. First, we stimulated human keratinocyte cell line HaCaT cells with psoriasis (pso)-mix, which is a cytokine pool (IL-17, IL-22, tumor necrosis factor-α, and IFN-γ) mimicking the in vitro "psoriasis-like" status and found that the ubiquitination of K17 was essential to stabilize its protein expression in pso-mix-treated HaCaT cells. Subsequently, tripartite motif-containing protein 21 was identified as the E3 ligase of K17, which ubiquitylated K17 via K63 linkage to maintain K17 stabilization. More importantly, we uncovered that K17 was a direct interactor of STAT3, and K17 ubiquitination could promote STAT3 activation in pso-mix-treated HaCaT cells. Our study demonstrated that targeting K17 ubiquitination may be a potential therapeutic approach by attenuating STAT3 signaling in psoriasis.

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Ubiquitination-proteasome system: A new player in the pathogenesis of psoriasis and clinical implications

Cited by 30 publications

References 76 publications

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Keratin 17 in disease pathogenesis: from cancer to dermatoses

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

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