The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Smith, Christopher J.; Berry, Donna M.; McGlade, C. Jane

doi:10.1242/jcs.116129

Cited by 49 publications

(78 citation statements)

References 41 publications

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“…Indeed, assays with a dominant-negative mutant of Rab7 impaired BCA2 function and led to increased Gag levels, and therefore, a substantial rescue in virus release. Moreover, BCA2 has recently been shown to route EGFR for endosomal sorting [42], [43], further corroborating the connection of BCA2 with the endo-lysosomal pathway.…”

Section: Discussionmentioning

confidence: 60%

BCA2/Rabring7 Targets HIV-1 Gag for Lysosomal Degradation in a Tetherin-Independent Manner

Nityanandam

Serra-Moreno

2014

PLoS Pathog

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BCA2 (Rabring7, RNF115 or ZNF364) is a RING-finger E3 ubiquitin ligase that was identified as a co-factor in the restriction imposed by tetherin/BST2 on HIV-1. Contrary to the current model, in which BCA2 lacks antiviral activity in the absence of tetherin, we found that BCA2 possesses tetherin-independent antiviral activity. Here we show that the N-terminus of BCA2 physically interacts with the Matrix region of HIV-1 and other retroviral Gag proteins and promotes their ubiquitination, redistribution to endo-lysosomal compartments and, ultimately, lysosomal degradation. The targeted depletion of BCA2 in tetherin-expressing and tetherin-deficient cells results in a significant increase in virus release and replication, indicating that endogenous BCA2 possesses antiviral activity. Therefore, these results indicate that BCA2 functions as an antiviral factor that targets HIV-1 Gag for degradation, impairing virus assembly and release.

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Section: Discussionmentioning

confidence: 60%

BCA2/Rabring7 Targets HIV-1 Gag for Lysosomal Degradation in a Tetherin-Independent Manner

Nityanandam

Serra-Moreno

2014

PLoS Pathog

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“…It is possible that RNF8 catalyzes an initial ubiquitylation of Ku80 and that the ubiquitin chain is then extended by RNF126. This scenario is supported by the recent observation that the zinc finger domain of RNF126 binds directly to ubiquitin (24).…”

Section: Discussionmentioning

confidence: 65%

“…Polyubiquitylation of the epidermal growth factor receptor (EGFR) on the endosomal membrane by RNF126 was thus shown to promote its lysosomal sorting and degradation (24). RNF126 also regulates trafficking of another membrane protein, the mannose-6-phosphate receptor, from endosomes to the Golgi complex in a manner dependent on its RING finger domain, although the substrate of RNF126 in this regulation was not identified (26).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair

Ishida

Nakagawa

Iemura

et al. 2017

Molecular and Cellular Biology

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Repair of damaged DNA is critical for maintenance of genetic information. In eukaryotes, DNA double-strand breaks (DSBs) are recognized by the Ku70-Ku80 heterodimer, which then recruits proteins that mediate repair by nonhomologous end joining (NHEJ). Prolonged retention of Ku70/80 at DSBs prevents completion of repair, however, with ubiquitylation of Ku80 having been implicated in Ku70/80 dissociation from DNA. Here, we identify RNF126 as a ubiquitin ligase that is recruited to DSBs and ubiquitylates Ku80, with UBE2D3 serving as an E2 enzyme. Knockdown of RNF126 prevented Ku70/80 dissociation from DSBs and inhibited break repair. Attenuation of Ku80 ubiquitylation by replacement of ubiquitylation site lysines with arginine residues delayed Ku70/80 release from chromatin after DSB induction by genotoxic insults. Together, our data indicate that RNF126 is a novel regulator of NHEJ that promotes completion of DNA repair by ubiquitylating Ku80 and releasing Ku70/80 from damaged DNA.KEYWORDS DNA repair, Ku80, RNF126, nonhomologous end joining (NHEJ), ubiquitylation D NA damage poses a threat to living organisms because they rely on the genetic code to execute cellular functions. Genomic integrity is maintained in the face of DNA damage by the operation of dedicated DNA repair machinery. In eukaryotic cells, DNA double-strand breaks (DSBs), which constitute the most deleterious type of DNA damage, are repaired by two major, mechanistically distinct pathways: homologous recombination (HR) and nonhomologous end joining (NHEJ). HR replaces lost or damaged DNA sequence with high fidelity in a manner dependent on the presence of an intact sister chromatid as a template. HR thus functions only during S and G 2 phases of the cell cycle, when a sister chromatid is available (1). In contrast, NHEJ is active throughout the cell cycle and repairs DSBs by directly ligating chromosome ends without the use of a DNA template. As a consequence of its mode of action, however, NHEJ is error prone (2).The NHEJ pathway is initiated on recognition of DSBs by chromatin-remodeling factors and the Ku70-Ku80 heterodimer, the latter of which recruits additional factors to process the DSBs for repair. The Ku heterodimer forms a ring-shaped toroidal structure, through which the broken end of DNA is threaded. Given its abundance and the high affinity of Ku70/80 for DNA ends, a specific mechanism is thought to be required to dislodge the heterodimer from DNA after the recruitment of repair proteins in order to prevent its inhibition of repair completion and postrepair recovery (3). In

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“…Previous study suggested that RNF126 interacted with the EGFR through a ubiquitin‐binding zinc finger domain and promoted the ubiquitylation of EGFR 9. To determine the function of RNF126 in tongue cancer development, we focused on the downstream signaling pathway of EGFR.…”

Section: Resultsmentioning

confidence: 99%

“…First, the substrates of RNF126, like p21 14, Bag6 15, and EGFR 9 are involved in oncogenesis. It promotes cell proliferation partially through degrading p21 14.…”

Section: Discussionmentioning

confidence: 99%

E3 Ubiquitin ligase RNF126 regulates the progression of tongue cancer

Wang

Zhao

et al. 2016

Cancer Medicine

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This study aims to analyze the role of RNF126 in the oncogenesis of tongue cancer. The cell proliferation and viability of human tongue cancer cells, SCC25 and SCC9 cells, were determined by cell counting and MTT assay, respectively. The effect of RNF126 on regulating AKT signaling pathway was analyzed through western blotting. The transplantation tumor model of nude mice was used to evaluate the tumorigenecity of RNF126. Knockdown of RNF126 inhibited the proliferation and viability of SCC9 and SCC25 cells. Inhibition of RNF126 also decreased the activity of AKT1 as well as its downstream molecules. Furthermore, RNF126 regulated the tumor volume on mice model. These data suggested that RNF126 might be related to the progression of tongue cancer through regulating AKT signaling pathway.

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The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Cited by 49 publications

References 41 publications

BCA2/Rabring7 Targets HIV-1 Gag for Lysosomal Degradation in a Tetherin-Independent Manner

BCA2/Rabring7 Targets HIV-1 Gag for Lysosomal Degradation in a Tetherin-Independent Manner

Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair

E3 Ubiquitin ligase RNF126 regulates the progression of tongue cancer

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