Dataset Information

CRL4B^DCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

ABSTRACT: Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1), and DCAF11 (DDB1 and CUL4 associated factor 11) in human osteosarcoma cells. In vitro and in vivo ubiquitination analyses indicated that CRL4B^DCAF11 E3 ligase was able to specifically ubiquitinate a CDK inhibitor-p21^Cip1 at K16, K154, K161 and K163 but not at K75 and K141. Knocking down any component of the CRL4B^DCAF11 complex, including CUL4B, DDB1 or DCAF11, using short hairpin RNAs (shRNAs) attenuated the ubiquitination level of p21^Cip1, inhibited osteosarcoma cell proliferation, led to cell cycle arrest at S phase, and decreased colony formation rate. Taken together, our data suggest that the CRL4B^DCAF11 complex represents a unique E3 ligase that promotes the ubiquitination of p21^Cip1 and regulates cell cycle progression in human osteosarcoma cells.

SUBMITTER: Chen Z

PROVIDER: S-EPMC5430835 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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CRL4B<sup>DCAF11</sup> E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

Chen Zhi Z Wang Kun K Hou Canglong C Jiang Kaibiao K Chen Bin B Chen Jianwei J Lao Lifeng L Qian Lie L Zhong Guibin G Liu Zude Z Zhang Caiguo C Shen Hongxing H

Scientific reports 20170426 1

Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1) ...[more]

PMID: 28446751

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Project description:The accessory protein ORF6 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key interferon (IFN) antagonist that strongly suppresses the production of primary IFN as well as the expression of IFN-stimulated genes. However, how host cells respond to ORF6 remains largely unknown. Our research of ORF6-binding proteins by pulldown revealed that E3 ligase components such as Cullin 4B (CUL4B), DDB1, and RBX1 are potential ORF6-interacting proteins. Further study found that the substrate recognition receptor PRPF19 interacts with CUL4B, DDB1, and RBX1 to form a CRL4B-based E3 ligase, which catalyzes ORF6 ubiquitination and subsequent degradation. Overexpression of PRPF19 promotes ORF6 degradation, releasing ORF6-mediated IFN inhibition, which inhibits SARS-CoV-2 replication. Moreover, we found that activation of CUL4B by the neddylation inducer etoposide alleviates lung lesions in a SARS-CoV-2 mouse infection model. Therefore, targeting ORF6 for degradation may be an effective therapeutic strategy against SARS-CoV-2 infection.IMPORTANCEThe cellular biological function of the ubiquitin-proteasome pathway as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. It is a powerful tool that host cells use to defend against viral infection. Some cellular proteins can function as restriction factors to limit viral infection by ubiquitin-dependent degradation. In this research, we identificated of CUL4B-DDB1-PRPF19 E3 Ubiquitin Ligase Complex can mediate proteasomal degradation of ORF6, leading to inhibition of viral replication. Moreover, the CUL4B activator etoposide alleviates disease development in a mouse infection model, suggesting that this agent or its derivatives may be used to treat infections caused by SARS-CoV-2. We believe that these results will be extremely useful for the scientific and clinic communities in their search for cues and preventive measures to combat the COVID-19 pandemic.

Dataset Information

CRL4B^DCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

Publications

CRL4B<sup>DCAF11</sup> E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

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Dataset Information

CRL4BDCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

Publications

CRL4B<sup>DCAF11</sup> E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CRL4B^DCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells.