Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction

Sawamura, Naoya; Wakabayashi, Satoru; Matsumoto, Kodai; Yamada, Haruka; Asahi, Toru

doi:10.1016/j.bbrc.2015.07.068

Cited by 16 publications

(22 citation statements)

References 32 publications

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“…Along with their function in the recruitment of neosubstrates for protein degradation, these IMiDs exhibit both teratogenic and pleiotropic antitumor effects (50). Under UPS dysfunction, CRBN is recruited to the aggresome and exhibits cytoprotective roles in a neuronal cell line (51). Further study reveals that CRBN interacts with sequestosome 1/p62 and prevents its interaction with polyubiquitinated proteins, thus reducing protein aggregates formed under proteasomal stress (42).…”

Section: Discussionmentioning

confidence: 99%

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Yang

Huang

Zhou

et al. 2018

Journal of Biological Chemistry

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Chronic inflammation is associated with multiple human disorders such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environment stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its non-enzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process. Here, we use quantitative proteomic approach to find that the major component of the activator protein 1 (AP-1) complex, c-Jun, is significantly down-regulated upon CRBN expression. Biochemical approaches further discover that CRBN interacts and partially colocalizes with c-Jun, promotes the formation of the K48-linked polyubiquitin chains on c-Jun, and thus enhances c-Jun degradation. We further reveal that CRBN attenuates the transcriptional activity of AP-1 complex and reduces the mRNA expression and protein level of several pro-inflammatory cytokines. Moreover, flow cytometry analyses show that CRBN attenuates the lipopolysaccharide (LPS)-induced apoptosis in the differentiated THP-1 cells. Through genetic manipulation and pharmacological inhibition, we uncover a new molecular mechanism by which CRBN regulates the inflammatory response and apoptosis induced by LPS. Our work and previous studies demonstrate that CRBN suppresses the inflammatory response by promoting or inhibiting the ubiquitination of two key molecules at different levels of the inflammatory cascade through the enzymatic function as a substrate receptor and the non-enzymatic function as a protein binding partner.

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Section: Discussionmentioning

confidence: 99%

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Yang

Huang

Zhou

et al. 2018

Journal of Biological Chemistry

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“…In addition to AMPKα, ubiquitin-proteasome system (UPS) dysfunction is another cause of ER stress [52]. A recent report indicates that CRBN is recruited to aggresomes and exerts cytoprotective effects against UPS dysfunction-induced cell death [61], suggesting that CRBN has a role in ER stress modulation independently of AMPK. Taken together, these results indicate that CRBN could also be a therapeutic target of ER stress-related disease.…”

Section: Endoplasmic Reticulum Stressmentioning

confidence: 99%

Cereblon in health and disease

Kim

Nyamaa

et al. 2016

Pflugers Arch - Eur J Physiol

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Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage. In this review, we discuss the various roles of CRBN in human health and disease and suggest avenues for further research to enhance our basic knowledge and clinical application of CRBN.

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“…Cells were transfected using PEI Max Reagent (Polysciences Inc., Warrington, PA) according to the manufacturer's instructions. A wild-type CRBN expression vector was already generated in our previous study [5].…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…Additionally, yeast two-hybrid screening has identified CRBN as a potential binding protein of the ClC channel, a voltagegated chloride channel that mediates degradation via the ubiquitin-proteasome dependent pathway [7,8]. Recently, we reported that CRBN is recruited to aggresomes and functions in cytoprotection against the ubiquitin-proteasome system-impaired condition [5]. These reports show that CRBN functions in alteration of ubiquitination and degradation of specific targets in the cytosol.…”

Section: Introductionmentioning

confidence: 96%

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

Wada

Asahi

Sawamura

2016

Biochemical and Biophysical Research Communications

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Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction

Cited by 16 publications

References 32 publications

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Cereblon in health and disease

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

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