The roles of cytosolic quality control proteins, SGTA and the BAG6 complex, in disease

Benarroch, Rashi; Austin, Jennifer M.; Ahmed, Fahmeda; Isaacson, Rivka L.

doi:10.1016/bs.apcsb.2018.11.002

Cited by 20 publications

(21 citation statements)

References 124 publications

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“…13 Several studies have linked BAG6 to cancer and autoimmune diseases. 18 Additionally, GET5 has been shown to suppress tumor growth and metastasis in a pancreatic tumor model. 19 Thus, the GET4/5/BAG6 complex is involved in multiple signaling processes.…”

Section: Discussionmentioning

confidence: 99%

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

Tambe

Shimada

et al. 2020

J of Inher Metab Disea

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The transmembrane domain recognition complex (TRC) targets cytoplasmic C‐terminal tail‐anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi, and mitochondria. It is composed of three proteins, GET4, BAG6, and GET5. We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70% to 90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age. We found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized that such transport would be disrupted in his fibroblasts, and discovered that retrograde (but not anterograde) transport was significantly reduced. Despite reduction in the three TRC proteins, their mRNA levels were unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA‐approved proteasome inhibitor, bortezomib (10 nM), restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations.

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Section: Discussionmentioning

confidence: 99%

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

Tambe

Shimada

et al. 2020

J of Inher Metab Disea

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“…Previous studies identified MAVS as a potential interacting partner of BAG6 (Antonicka et al, 2020; Li et al, 2011), which typically acts downstream of SGTA (Farkas and Bohnsack, 2021; Hegde and Keenan, 2021). We therefore extended our co-immunoprecipitation study and found that MAVS is also an endogenous client of the BAG6 protein quality control complex (Benarroch et al, 2019) (Fig. 3A; Fig.…”

Section: Resultsmentioning

confidence: 70%

“…ATP13A1 is an ER-resident P5A-ATPase that has been implicated in the extraction of mitochondrial TA proteins including MAVS and OMP25 that can mislocalise to the ER membrane (McKenna et al, 2020). Given the ability of Bag6 and SGTA to bind membrane protein substrates that are dislocated into the cytosol via the pathways responsible for ERAD (Benarroch et al, 2019), we postulated that BAG6 may bind MAVS after its ATP13A1-mediated dislocation from the ER membrane.…”

Section: Atp13a1 Deficiency Does Not Affect the Bag6-mavs Interactionmentioning

confidence: 99%

Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex

Roboti

Lawless

High

2021

Preprint

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The heterotrimeric BAG6 complex coordinates the direct handover of newly synthesised tail-anchored (TA) membrane proteins from an SGTA-bound preloading complex to the endoplasmic reticulum (ER) delivery component TRC40. In contrast, defective precursors, including aberrant TA proteins, form a stable complex with this cytosolic protein quality control factor, enabling such clients to be either productively re-routed or selectively degraded. We identify the mitochondrial TA protein MAVS (mitochondrial antiviral-signalling protein) as an endogenous client of both SGTA and the BAG6 complex. Our data suggest that the BAG6 complex binds to a cytosolic pool of MAVS before its misinsertion into the ER membrane, from where it can subsequently be removed via ATP13A1-mediated dislocation. This BAG6- associated fraction of MAVS is dynamic and responds to the activation of an innate immune response, suggesting that BAG6 may modulate the pool of MAVS that is available for coordinating the cellular response to viral infection.SUMMARY STATEMENTMitochondrial antiviral-signalling (MAVS) protein is a favoured client of the cytosolic BAG6 complex. We discuss how this dynamic interaction may modulate MAVS biogenesis at signalling membranes.

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“…Our results further established that all of the BAG6 complex subunits are required for proper proteasome activity. The role of the BAG6 complex in proteasome regulation is rather unexplored as it is mostly known for its role in tail-anchored (TA) transmembrane protein sorting and in quality control [25]. In these cellular processes, the BAG6 complex acts as a chaperone for nascent transmembrane proteins and is instrumental for targeting TA transmembrane proteins to the ER.…”

Section: Fbxo7 and The Bag6 Complex Interact And Regulate Proteasome Activitymentioning

confidence: 99%

The parkinsonism-associated protein FBXO7 cooperates with the BAG6 complex in proteasome function and controls the subcellular localization of the complex

Wang

Crnković

Preisinger

et al. 2021

Biochemical Journal

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The regulation of proteasome activity is essential to cellular homeostasis and defects have been implicated in various disorders including Parkinson disease. The F-box protein FBXO7 has been implicated in early-onset parkinsonism and has previously been shown to have a regulatory role in proteasome activity and assembly. Here, we report the association of the E3 ubiquitin ligase FBXO7-SCF (SKP1, cullin-1, F-box protein) with the BAG6 complex, consisting of the subunits BAG6, GET4 and UBL4A. We identify the subunit GET4 as a direct interactor of FBXO7 and we show that the subunits GET4 and UBL4A are required for proper proteasome activity. Our findings demonstrate reduced binding of FBXO7 variants to GET4 and that FBXO7 variants bring about reduced proteasome activity. In addition, we find that GET4 is a non-proteolytic substrate of FBXO7, that binding of GET4 to BAG6 is enhanced in the presence of active FBXO7-SCF and that the cytoplasmic localization of the BAG6 complex is dependent on the E3 ubiquitin ligase activity. Taken together, our study shows that the parkinsonism-associated FBXO7 cooperates with the BAG6 complex in proteasome function and determines the subcellular localization of this complex.

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The roles of cytosolic quality control proteins, SGTA and the BAG6 complex, in disease

Cited by 20 publications

References 124 publications

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex

The parkinsonism-associated protein FBXO7 cooperates with the BAG6 complex in proteasome function and controls the subcellular localization of the complex

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