The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation

Lee, Chih-Yuan; Lai, Ting-Yu; Tsai, Min Kuang; Chang, Yung-Chi; Ho, Yu-Hsin; Yu, I-Shing; Yeh, Tzu-Wen; Chou, Chih-Chang; Lin, Yousheng; Lawrence, Toby; Hsu, Li-Chung

doi:10.1038/ncomms15502

Cited by 41 publications

(43 citation statements)

References 58 publications

(77 reference statements)

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“…Though the precise cellular roles of ZNRF1 remain to be deciphered, it has been found to co-localize with tubulin in cells and ubiquitinates protein kinase B (Akt1), glutamine synthase, and the α subunit of Na + /K + pump [ 16 – 18 ]. Recent studies further implicate ZNRF1 in modulating inflammation via ubiquitination of caveolin-1 establishing the importance of this protein in immune response [ 19 ]. Besides Ube2N, ZNRF1 also co-elutes with minor amounts of Ube2Ds and Ube2W suggesting high E2 affinity of this E3 ligase [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications

Behera

Naskar

Agarwal

et al. 2018

Biochemical Journal

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RING (Really Interesting New Gene) domains in ubiquitin RING E3 ligases exclusively engage ubiquitin (Ub)-loaded E2s to facilitate ubiquitination of their substrates. Despite such specificity, all RINGs characterized till date bind unloaded E2s with dissociation constants (Kds) in the micromolar to the sub-millimolar range. Here, we show that the RING domain of E3 ligase ZNRF1, an essential E3 ligase implicated in diverse cellular pathways, binds Ube2N with a Kd of ∼50 nM. This high-affinity interaction is exclusive for Ube2N as ZNRF1 interacts with Ube2D2 with a Kd of ∼1 µM, alike few other E3s. The crystal structure of ZNRF1 C-terminal domain in complex with Ube2N coupled with mutational analyses reveals the molecular basis of this unusual affinity. We further demonstrate that the ubiquitination efficiency of ZNRF1 : E2 pairs correlates with their affinity. Intriguingly, as a consequence of its high E2 affinity, an excess of ZNRF1 inhibits Ube2N-mediated ubiquitination at concentrations ≥500 nM instead of showing enhanced ubiquitination. This suggests a novel mode of activity regulation of E3 ligases and emphasizes the importance of E3-E2 balance for the optimum activity. Based on our results, we propose that overexpression-based functional analyses on E3 ligases such as ZNRF1 must be approached with caution as enhanced cellular levels might result in aberrant modification activity.

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Section: Introductionmentioning

confidence: 99%

Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications

Behera

Naskar

Agarwal

et al. 2018

Biochemical Journal

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“…IFNinduced CH25H shows antiviral activities and can positively and negatively regulate the inflammatory responses of mammals (78). Mammalian TNFRSF11B (alias Osteoprotegerin), ZNRF1 and CLDN4 regulate LPS-induced cytokine and/or inflammatory responses (79)(80)(81). GVINP1 is an IFN-induced GTPase, regulating oxidative and inflammasome-related antimicrobial activities of cells in mammals (82).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of the Adaptive and Innate Immune Responses of Atlantic Salmon to Renibacterium salmoninarum Infection

et al. 2020

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Bacterial Kidney Disease (BKD), which is caused by a Gram-positive, intracellular bacterial pathogen (Renibacterium salmoninarum), affects salmonids including Atlantic salmon (Salmo salar). However, the transcriptome response of Atlantic salmon to BKD remained unknown before the current study. We used a 44K salmonid microarray platform to characterise the global gene expression response of Atlantic salmon to BKD. Fish (∼54 g) were injected with a dose of R. salmoninarum (H-2 strain, 2 × 10 8 CFU per fish) or sterile medium (control), and then head kidney samples were collected at 13 days post-infection/injection (dpi). Firstly, infection levels of individuals were determined through quantifying the R. salmoninarum level by RNA-based TaqMan qPCR assays. Thereafter, based on the qPCR results for infection level, fish (n = 5) that showed no (control), higher (H-BKD), or lower (L-BKD) infection level at 13 dpi were subjected to microarray analyses. We identified 6,766 and 7,729 differentially expressed probes in the H-BKD and L-BKD groups, respectively. There were 357 probes responsive to the infection level (H-BKD vs. L-BKD). Several adaptive and innate immune processes were dysregulated in R. salmoninarum-infected Atlantic salmon. Adaptive immune pathways associated with lymphocyte differentiation and activation (e.g., lymphocyte chemotaxis, T-cell activation, and immunoglobulin secretion), as well as antigen-presenting cell functions, were shown to be differentially regulated in response to BKD. The infection level-responsive transcripts were related to several mechanisms such as the JAK-STAT signalling pathway, B-cell differentiation and interleukin-1 responses. Sixty-five microarray-identified transcripts were subjected to qPCR validation, and they showed the same fold-change direction as microarray results. The qPCRvalidated transcripts studied herein play putative roles in various immune processes including pathogen recognition (e.g., tlr5), antibacterial activity (e.g., hamp and camp), regulation of immune responses (e.g., tnfrsf11b and socs1), T-/B-cell differentiation (e.g., ccl4, irf1 and ccr5), T-cell functions (e.g., rnf144a, il13ra1b and tnfrsf6b), and Eslamloo et al. Atlantic Salmon Response to BKD antigen-presenting cell functions (e.g., fcgr1). The present study revealed diverse immune mechanisms dysregulated by R. salmoninarum in Atlantic salmon, and enhanced the current understanding of Atlantic salmon response to BKD. The identified biomarker genes can be used for future studies on improving the resistance of Atlantic salmon to BKD.

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“…In macrophages, the association of Cav-1 to TLR4 diminishes the production of pro-inflammatory cytokines and enhances the production of anti-inflammatory cytokines, at least in part, in a p38-dependent manner ( 25 ). Upon TLR4 activation, the ubiquitin ligase ZNRF1 ubiquitinates Cav-1 leading to its degradation, resulting in increased production of pro-inflammatory cytokines and inhibition of anti-inflammatory ones ( 26 ). TLR4 activation by LPS also stimulates heme oxygenase-1 producing carbon oxide (CO), which has known anti-inflammatory activity.…”

Section: Cav-1 Activities In Inflammationmentioning

confidence: 99%

Caveolin-1 and Caveolin-2 Can Be Antagonistic Partners in Inflammation and Beyond

Almeida

2017

Front. Immunol.

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Caveolins, encoded by the CAV gene family, are the main protein components of caveolae. In most tissues, caveolin-1 (Cav-1) and caveolin-2 (Cav-2) are co-expressed, and Cav-2 targeting to caveolae depends on the formation of heterooligomers with Cav-1. Notwithstanding, Cav-2 has unpredictable activities, opposing Cav-1 in the regulation of some cellular processes. While the major roles of Cav-1 as a modulator of cell signaling in inflammatory processes and in immune responses have been extensively discussed elsewhere, the aim of this review is to focus on data revealing the distinct activity of Cav-1 and Cav-2, which suggest that these proteins act antagonistically to fine-tune a variety of cellular processes relevant to inflammation.

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The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation

Cited by 41 publications

References 58 publications

Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications

Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications

Transcriptomic Profiling of the Adaptive and Innate Immune Responses of Atlantic Salmon to Renibacterium salmoninarum Infection

Caveolin-1 and Caveolin-2 Can Be Antagonistic Partners in Inflammation and Beyond

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