Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK/STAT Signaling

Lin, Li; Lei, Qingsong; Zhang, Shujun; Kong, Lingna; Qin, Bo

doi:10.1371/journal.pone.0156496

Cited by 35 publications

(42 citation statements)

References 33 publications

(35 reference statements)

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“…The expression of USP18 is strongly induced by type I and type III interferons [2][3][4][5], by the Toll-like receptor (TLR) agonists LPS [6][7][8] and polyI:C [6] (synthetic analogy of dsRNA) and by TNFα [7]. In line with this, USP18 RNA and protein levels in cells are increased after viral or bacterial infection [9][10][11][12]. USP18 specifically deconjugates the ubiquitin-like protein (Ubl) ISG15 (interferon-stimulated gene 15) from target proteins [13][14][15].…”

Section: Introductionmentioning

confidence: 81%

USP18 – a multifunctional component in the interferon response

2018

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Ubiquitin-specific proteases (USPs) represent the largest family of deubiquitinating enzymes (DUB). These proteases cleave the isopeptide bond between ubiquitin and a lysine residue of a ubiquitin-modified protein. USP18 is a special member of the USP family as it only deconjugates the ubiquitin-like protein ISG15 (interferon-stimulated gene (ISG) 15) from target proteins but is not active towards ubiquitin. Independent of its protease activity, USP18 functions as a major negative regulator of the type I interferon response showing that USP18 is – at least – a bifunctional protein. In this review, we summarise our current knowledge of protease-dependent and -independent functions of USP18 and discuss the structural basis of its dual activity.

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Section: Introductionmentioning

confidence: 81%

USP18 – a multifunctional component in the interferon response

2018

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“…18 Moreover, transfecting human hepatoblastoma HepG2 cells with hepatitis B virus (HBV) genome increased the expression of USP18 in those cells. 19 The Usp18 gene is rapidly and strongly upregulated after viral infection or by type I and type III IFNs, 1,6,13,19,20 lipopolysaccharide (LPS), 21,22 tumor necrosis factor alpha (TNF-α), 22 or genotoxic stress 13,23 (Figure 2a). USP18 is degraded by proteasomes.…”

Section: Expression Of Usp18mentioning

confidence: 99%

Multiple functions of USP18

et al. 2016

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Since the discovery of the ubiquitin system and the description of its important role in the degradation of proteins, many studies have shown the importance of ubiquitin-specific peptidases (USPs). One special member of this family is the USP18 protein (formerly UBP43). In the past two decades, several functions of USP18 have been discovered: this protein is not only an isopeptidase but also a potent inhibitor of interferon signaling. Therefore, USP18 functions as 'a' maestro of many biological pathways in various cell types. This review outlines multiple functions of USP18 in the regulation of various immunological processes, including pathogen control, cancer development, and autoimmune diseases.

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“…The control shRNA‐NC and shRNA‐USP18 were transduced into Hepg2.2.15 cells to knockdown USP18. The expression of USP18 was confirmed using qRT‐PCR and Western blot as described in our previous work . Accordingly, we addressed the question of what genes and pathways were regulated by USP18 knockdown.…”

Section: Resultsmentioning

confidence: 98%

Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells

et al. 2017

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In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2.2.15 stably expressing USP18-shRNA cells versus control cells using the Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Microarray analysis indicated that genes involved in regulation of thyroid hormone signaling pathway, complement, and coagulation cascades, PERK-mediated unfolded protein response, and insulin-like growth factor-activated receptor activity were significantly altered after USP18 knockdown for 72 h. Furthermore, genes involved in hepatocyte proliferation, liver fibrosis, such as cell cycle regulatory gene CCND1, were also altered after USP18 knockdown in Hepg2.2.15 cells. In conclusion, USP18 is critical for regulating the replication of HBV in Hepg2.2.15 cells, which suggest that USP18 may be a candidate target for HBV treatment.

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Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK/STAT Signaling

Cited by 35 publications

References 33 publications

USP18 – a multifunctional component in the interferon response

USP18 – a multifunctional component in the interferon response

Multiple functions of USP18

Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells

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