Cytosolic Quality Control of Mislocalized Proteins Requires RNF126 Recruitment to Bag6

Rodrigo-Brenni, Monica C.; Gutierrez, Erik; Hegde, Ramanujan S.

doi:10.1016/j.molcel.2014.05.025

Cited by 158 publications

(215 citation statements)

References 51 publications

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“…The redundancy in cellular chaperone networks could, however, mask the contribution of BAG6 to this pathway. BAG6 together with its E3 ligase RNF126 indeed resembles the HSP70/HSP90 chaperone system, which cooperates with the E3 ligase CHIP to promote substrate degradation (Connell et al, 2001;Rodrigo-Brenni et al, 2014). The finding that BAG6 substrates could still be degraded in the absence of BAG6 and/or RNF126, albeit more slowly and less efficiently, further indicates the existence of one or several redundant pathways (Rodrigo-Brenni et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

“…While assisting in protein biosynthesis on the one hand, BAG6 also mediates degradation of mislocalized nascent chains (Hessa et al, 2011) and ERAD substrates (Claessen and Ploegh, 2011;Claessen et al, 2014;Payapilly and High, 2014;Wang et al, 2011). Moreover, Rodrigo-Brenni et al (2014) recently described RNF126 as an E3 ligase interacting with BAG6 and specifically ubiquitylating chaperone bound client proteins (Rodrigo-Brenni et al, 2014). The fact that BAG6 has been described as a "holdase" conferring no evident folding activity onto its substrates makes this chaperone even more interesting with regard to protein quality control and degradation (Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…BAG6 together with its E3 ligase RNF126 indeed resembles the HSP70/HSP90 chaperone system, which cooperates with the E3 ligase CHIP to promote substrate degradation (Connell et al, 2001;Rodrigo-Brenni et al, 2014). The finding that BAG6 substrates could still be degraded in the absence of BAG6 and/or RNF126, albeit more slowly and less efficiently, further indicates the existence of one or several redundant pathways (Rodrigo-Brenni et al, 2014). Moreover, BAG6 and HSP70 seem to compete for substrate binding as BAG6 could prevent HSP70-mediated refolding of denatured luciferase in an in vitro assay (Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer

Basler

Groettrup

2016

Molecular Immunology

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a b s t r a c tAntigen processing for direct presentation on MHC class I molecules is a multistep process requiring the concerted activity of several cellular complexes. The essential steps at the beginning of this pathway, namely protein synthesis at the ribosome and degradation via the proteasome, have been known for years. Nevertheless, there is a considerable lack of factors identified to function between protein synthesis and degradation during antigen processing. Here, we analyzed the impact of the chaperone BAG6 on MHC class I cell surface expression and presentation of virus-derived peptides. Although an essential role of BAG6 in antigen processing has been proposed previously, we found BAG6 to be dispensable in this pathway. Still, interaction of BAG6 and the model antigen tyrosinase was enhanced during proteasome inhibition pointing towards a role of BAG6 in antigen degradation. Redundant chaperone pathways potentially mask the contribution of BAG6 to antigen processing and presentation.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer

Basler

Groettrup

2016

Molecular Immunology

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“…This suggests that the quality control machinery discovered here complements known pathways that ensure proteostasis in human cells. The enzymes and effectors of K11/K48-specific quality control appear to be well suited to safeguard new protein synthesis: UBR5 contains an RNA-binding domain that might direct it to translating polysomes, while effectors of this pathway, such as BAG6, p97, and the proteasome, frequently operate in association with the ribosome (Brandman et al, 2012; Hessa et al, 2011; Rodrigo-Brenni et al, 2014; Sha et al, 2009; Turner and Varshavsky, 2000; Verma et al, 2013). These observations imply that K11/K48-specific quality control immediately checks the integrity of newly synthesized proteins to prevent their deleterious aggregation.…”

Section: Discussionmentioning

confidence: 99%

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

Yau

Doerner

Castellanos³

et al. 2017

Cell

265

276

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Summary Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation- prone proteins. By revealing key roles of K11/K48-linked chains in cell cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.

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“…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). Mislocalized proteins that contain a transmembrane domain but fail to enter the endoplasmic reticulum are also polyubiquitylated by RNF126 in the cytosol for subsequent degradation (27). These observations show that RNF126 regulates trafficking of membrane proteins at multiple steps in the cytosol, and combined with our present results, they suggest that nucleocytoplasmic shuttling of RNF126 plays a key role in regulation of its function.…”

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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Cytosolic Quality Control of Mislocalized Proteins Requires RNF126 Recruitment to Bag6

Cited by 158 publications

References 51 publications

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

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

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