Carboxyl Terminus of HSC70-interacting Protein (CHIP) Down-regulates NF-κB-inducing Kinase (NIK) and Suppresses NIK-induced Liver Injury

Protein arginine methyltransferase 5 (PRMT5) is an important member of the protein arginine methyltransferase family that regulates many cellular processes through epigenetic control of target gene expression. Because of its overexpression in a number of human cancers and its essential role in cell proliferation, transformation, and cell cycle progression, PRMT5 has been recently proposed to function as an oncoprotein in cancer cells. However, how its expression is regulated in cancer cells remains largely unknown. We have previously demonstrated that the transcription of PRMT5 can be negatively regulated by the PKC/c-Fos signaling pathway through modulating the transcription factor NF-Y in prostate cancer cells. In the present study, we demonstrated that PRMT5 undergoes polyubiquitination, possibly through multiple lysine residues. We also identified carboxyl terminus of heat shock cognate 70-interacting protein (CHIP), an important chaperone-dependent E3 ubiquitin ligase that couples protein folding/refolding to protein degradation, as an interacting protein of PRMT5 via mass spectrometry. Their interaction was further verified by co-immuoprecipitation, GST pull-down, and bimolecular fluorescence complementation (BiFC) assay. In addition, we provided evidence that the CHIP/chaperone system is essential for the negative regulation of PRMT5 expression via K48-linked ubiquitin-dependent proteasomal degradation. Given that down-regulation of CHIP and overexpression of PRMT5 have been observed in several human cancers, our finding suggests that down-regulation of CHIP may be one of the mechanisms underlying PRMT5 overexpression in these cancers.

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“…6C). Therefore, it remains to be investigated whether CHIP may cooperate with other E3 ligases to ubiquitinate PRMT5 [58]. …”

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5

Zhang

Zeng

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…(7) and Jiang et al . (8). STOP‐NIK male mice (8 wk) were infected with Ad‐cre (2 × 10 11 viral particles per mouse) via tail vein injection and then were injected with B022 (30 μg/kg bodyweight) or an equal volume of vehicle via tail vein twice a day for 10 d. For the CCl 4 ‐induced liver injury mouse model, wild‐type (WT) C57BL/6 WT mice were intraperitoneally injected with CCl4 (2.5 μl/kg bodyweight, 10% in olive oil) and then injected with B022 (25 μg/kg bodyweight) or an equal volume of vehicle via tail vein at 0, 3, 6, and 9 h after CCl4 injection.…”

Section: Methodsmentioning

confidence: 99%

A small‐molecule inhibitor of NF‐κB‐inducing kinase (NIK) protects liver from toxin‐induced inflammation, oxidative stress, and injury

Ren

Jia

et al. 2016

FASEB j.

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Potent and selective chemical probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chemical probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-molecule inhibitor of NIK, B022, was found to be a potent and selective chemical probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo Furthermore, in vivo administration of B022 protected against not only NIK but also CCl-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.-Ren, X., Li, X., Jia, L., Chen, D., Hou, H., Rui, L., Zhao, Y., Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.

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“…The 3 putative Snail1 binding sites were replaced with “CTAATG” to generate Δ1, Δ2, Δ3, or Δ123 luciferase reporters, using site-directed mutagenesis kits (Stratagene, La Jolla, CA). ATGL luciferase reporter plasmids were cotransfected with Snail1 expression vectors into HEK293 or 3T3-L1 cells (Jiang et al, 2015). Luciferase activities were measured 48 h after transfection using a kit (Progema, Madison, WI), and normalized to the activities of coexpressed β-gal (internal control).…”

Section: Methodsmentioning

confidence: 99%

Adipose Snail1 Regulates Lipolysis and Lipid Partitioning by Suppressing Adipose Triacylglycerol Lipase Expression

et al. 2016

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Summary Lipolysis provides metabolic fuel; however, aberrant adipose lipolysis results in ectopic lipid accumulation and lipotoxicity. While adipose triacylglycerol lipase (ATGL) catalyzes the first step of lipolysis, its regulation is not fully understood. Here, we demonstrate that adipocyte Snail1 suppresses both ATGL expression and lipolysis. Adipose Snail1 levels are higher in fed than in fasted mice, and higher in obese as opposed to lean mice. Insulin increases Snail1 levels in both murine and human adipocytes wherein Snail1 binds to the ATGL promoter to repress its expression. Importantly, adipocyte-specific deletion of Snail1 increases adipose ATGL expression and lipolysis, resulting in decreased fat mass and increased liver fat content in mice fed either a normal chow diet or a high fat diet. Thus, we have identified a Snail1-ATGL axis that regulates adipose lipolysis and fatty acid release, thereby governing lipid partitioning between adipose and non-adipose tissues.

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Carboxyl Terminus of HSC70-interacting Protein (CHIP) Down-regulates NF-κB-inducing Kinase (NIK) and Suppresses NIK-induced Liver Injury

Cited by 36 publications

References 37 publications

The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5

The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5

A small‐molecule inhibitor of NF‐κB‐inducing kinase (NIK) protects liver from toxin‐induced inflammation, oxidative stress, and injury

Adipose Snail1 Regulates Lipolysis and Lipid Partitioning by Suppressing Adipose Triacylglycerol Lipase Expression

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