SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation

Kuang, Peng; Tan, Mingjia; Zhou, Weihua; Zhang, Qiang; Sun, Yi

doi:10.1038/srep37441

Cited by 33 publications

(24 citation statements)

References 56 publications

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“…1d and S1H). Interestingly, silencing of CUL5 also increased β-TrCP1 levels, which is consistent with a recently published study that SAG-CUL5 negatively regulates β-TrCP1 levels via K11-linkage mediated ubiquitination [13]. In addition, β-TrCP2 levels were also increased upon CUL3 silencing ( Fig.…”

Section: Resultssupporting

confidence: 92%

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

et al. 2019

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β-transducin repeat-containing protein (β-TrCP), one of the best-characterized substrate recognition components of the SKP1-CUL1-F-box (SCF) E3 ligase, has two distinct paralogs, β-TrCP1 and β-TrCP2, expressed in mammals. Through governing the ubiquitination and degradation of numerous key regulators, β-TrCP1/2 regulates various cellular physiological and pathological processes. However, whether and how these two proteins cross talk and whether they regulate cell autophagy and proliferation in different manners is completely unknown. Herein, we report that β-TrCP1 and β-TrCP2 are the physiological substrates of SCF E3 ligase and target each other for degradation that is dependent on their β-TrCP degron sequences. Furthermore, glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1. Finally, we found that β-TrCP2, not β-TrCP1, preferentially degrades DEPTOR and REDD1, the inhibitors of mTORC1, to activate mTORC1, leading to autophagy inhibition and cell growth. Thus, our study demonstrates that β-TrCP1 and β-TrCP2 mutually target each other for degradation and that β-TrCP2 acts as a dominant paralog in the regulation of cell autophagy and growth, which might be a promising anticancer target.

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Section: Resultssupporting

confidence: 92%

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

et al. 2019

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“…4 ). The stability of β-TrCP was reported to be subjected to the regulation by several E3 ubiquitin ligases, including SMURF2 32 , SKP2 33 , and SAG-CRL5 34 . At the present time, it is unknown how siRPS27L promotes β-TrCP degradation.…”

Section: Discussionmentioning

confidence: 99%

Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis

Xiong

Liu

et al. 2018

Cell Death Dis

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RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.

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“…Among them, CDC34 and UBE2J1 are mainly responsible for K48 linked ubiquitination [ 15 ]. UBE2S mediates K11 linked ubiquitination [ 34 , 35 ]. UBE2V1, formed a heterodimer with UBE2N, mediates K63 ubiquitination which are reported to be important in activation of RIG-I and NF-κB signaling [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection

Feng

Deng

et al. 2018

Virol J

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BackgroundViral infection activates innate immune pathways and interferons (IFNs) play a pivotal role in the outcome of a viral infection. Ubiquitin modifications of host and viral proteins significantly influence the progress of virus infection. Ubiquitin-conjugating enzyme E2s (UBE2) have the capacity to determine ubiquitin chain topology and emerge as key mediators of chain assembly.MethodsIn this study, we screened the functions of 34 E2 genes using an RNAi library during Dengue virus (DENV) infection. RNAi and gene overexpression approaches were used to study the gene function in viral infection and interferon signaling.ResultsWe found that silencing UBE2J1 significantly impaired DENV infection, while overexpression of UBE2J1 enhanced DENV infection. Further studies suggested that type I IFN expression was significantly increased in UBE2J1 silenced cells and decreased in UBE2J1 overexpressed cells. Reporter assay suggested that overexpression of UBE2J1 dramatically suppressed RIG-I directed IFNβ promoter activation. Finally, we have confirmed that UBE2J1 can facilitate the ubiquitination and degradation of transcription factor IFN regulatory factor 3 (IRF3).ConclusionThese results suggest that UBE2 family member UBE2J1 can negatively regulate type I IFN expression, thereby promote RNA virus infection.Electronic supplementary materialThe online version of this article (10.1186/s12985-018-1040-5) contains supplementary material, which is available to authorized users.

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SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation

Cited by 33 publications

References 56 publications

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection

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