Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus

Liu, Junli; Huang, Xinfang; Hao, Shumeng; Wang, Yan; Liu, Manman; Xu, Jing; Zhang, Xingli; Tao, Yu; Gan, Shucheng; Dai, Dongfang; Luo, Xuan; Lu, Qingyan; Mao, Chaoming; Zhang, Yanyun; Shen, Nan; Li, Bin; Huang, Mingzhu; Zhu, Xiaoyan; Jin, Jin; Cheng, Xuhong; Sun, Shao Cong; Xiao, Yichuan

doi:10.1038/s41467-018-03530-3

Cited by 58 publications

(75 citation statements)

References 49 publications

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“…Interestingly, TLR7 expression was significantly upregulated in C2 and downregulated in C3 (Figure d). PELI1 (encoding Pellino1) is a TLR3‐inducible negative regulator of noncanonical NF‐κB, and the expression of PELI1 was negatively correlated with disease severity . In our stratification, PELI1 was not significantly underexpressed in any SLE clusters, but was upregulated in C3 and C4, possibly induced for NF‐κB regulation (Figure e).…”

Section: Resultsmentioning

confidence: 59%

“…inducible negative regulator of noncanonical NF-jB, and the expression of PELI1 was negatively correlated with disease severity. 24,25 In our stratification, PELI1 was not significantly underexpressed in any SLE clusters, but was upregulated in C3 and C4, possibly induced for NF-jB regulation (Figure 4e). TSC22D3 (also known as GILZ) was identified as a negative regulator of B cells, and lack of GILZ drives autoimmune disease (Figure 4e).…”

Section: Resultsmentioning

confidence: 60%

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Machine learning applied to whole‐blood RNA‐sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

Figgett

Monaghan

et al. 2019

Clin & Trans Imm

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Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus, responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the computational analysis of patients’ whole‐blood transcriptomes. Methods We applied machine learning approaches to RNA‐sequencing (RNA‐seq) data sets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta‐analysis on three recently published whole‐blood RNA‐seq data sets was carried out, and an additional similar data set of 30 patients with SLE and 29 healthy donors was incorporated in this study; a total of 161 patients with SLE and 57 healthy donors were analysed. Results Examination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease‐related genes relative to clinical presentation. Moreover, gene signatures correlated with flare activity were successfully identified. Conclusion Given that SLE disease heterogeneity is a key challenge hindering the design of optimal clinical trials and the adequate management of patients, our approach opens a new possible avenue addressing this limitation via a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy allowing the identification of separate molecular mechanisms underpinning disease in SLE. Further, this approach may have a use in understanding the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.

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Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 60%

Machine learning applied to whole‐blood RNA‐sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

Figgett

Monaghan

et al. 2019

Clin & Trans Imm

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“…The PELI1 is an E3 ubiquitin ligase; which has been reported to suppress the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling . The GO term and pathway enrichment for PELI1 correspond to IL‐1 signaling pathway (Table S4).…”

Section: Discussionmentioning

confidence: 99%

“…The GO term and pathway enrichment for PELI1 correspond to IL‐1 signaling pathway (Table S4). The PELI1 gets associated with NF‐κB inducing Kinase (NIK) and leads the ubiquitination and degradation of NIK at lys‐48 . The miRNA‐mRNA interaction analysis may suggest the role of hsa‐mir‐21 and PELI1 during CHIKV infection.…”

Section: Discussionmentioning

confidence: 99%

“…49 The PELI1 is an E3 ubiquitin ligase; which has been reported to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. 50 The GO term and pathway enrichment for PELI1 correspond to IL-1 signaling pathway (Table S4). The PELI1 gets associated with NF-κB inducing Kinase (NIK) and leads the ubiquitination and degradation of NIK at lys-48.…”

Section: Discussionmentioning

confidence: 99%

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Chikungunya virus modulates the miRNA expression patterns in human synovial fibroblasts

Agrawal

Pandey

Rastogi

et al. 2019

Journal of Medical Virology

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Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes. CHIKV infection leads to polyarthritis and polyarthralgia among patients. The synovial fibroblasts are the primary target for CHIKV. The microRNAs (miRNAs) are the small endogenous noncoding RNAs which posttranscriptionally regulate the expression of genes by binding to their target messenger RNAs (mRNAs) through their 3′‐untranslated regions. The miRNAs are the key regulators for various pathological processes including viral infection, cancer, cardiovascular disease, and neurodegeneration. This study was designed to dissect out the roles of miRNAs during CHIKV (Ross Strain E1: A226V) infection in primary human synovial fibroblasts. The miRNA microarray profiling was performed on the primary human synovial fibroblasts infected by CHIKV. The gene target prediction analysis, enrichment, and network analysis were performed by various bioinformatics analyses. The subset of 26 differentially expressed microRNAs (DEMs) were identified through microarray profiling and were further screened for gene predictions, Gene Ontology, pathway enrichment, and miRNA‐mRNA network using various bioinformatics tools. The bioinformatics analysis indicates the role of DEMs by suppressing the immune response which may contribute to CHIKV persistence in human primary synovial fibroblasts. Our study provides the plausible roles of DEMs, miRNAs, and mRNA interactions and pathways involved in the molecular pathogenesis of CHIKV.

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PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF‐κB in esophageal squamous cancer

et al. 2021

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The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1-mediated IR-induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)-linked polyubiquitination and degradation of NF-κB-inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF-κB pathway, thereby inhibiting IR-induced activation of the noncanonical NF-κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF-κB-induced expression of the anti-apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR-induced apoptosis signaling pathway and ultimately promoting IRinduced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis-resistant effect in PELI1-knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR-induced noncanonical NF-κB expression.

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Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus

Cited by 58 publications

References 49 publications

Machine learning applied to whole‐blood RNA‐sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

Machine learning applied to whole‐blood RNA‐sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

Chikungunya virus modulates the miRNA expression patterns in human synovial fibroblasts

PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF‐κB in esophageal squamous cancer

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