The VCP-UBXN1 Complex Mediates Triage of Ubiquitylated Cytosolic Proteins Bound to the BAG6 Complex

Ganji, Rakesh; Mukkavalli, Sirisha; Somanji, Flavio; Raman, Malavika

doi:10.1128/mcb.00154-18

Cited by 29 publications

(48 citation statements)

References 30 publications

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“…In this context, it should be interesting to note that RNF126 has a role in membrane protein sorting in HeLa cells . Recently, it was reported that some BAG6 client proteins are degraded by the UBXN1‐mediated pathway . Therefore, it might be interesting to examine this possibility with Rab8a (T22N) as a substrate.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic control of Rab family small GTP ases through BAG 6

et al. 2019

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Rab family small GTP ases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. GDP ‐bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG 6 ( BAT 3/Scythe) predominantly recognizes a cryptic portion of GDP ‐associated Rab8a, while its major GTP ‐bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG 6 and the degradation of GDP ‐Rab8a via the ubiquitin‐proteasome system. BAG 6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. BAG 6 binds not only Rab8a but also a functionally distinct set of Rab family proteins, and is also required for the correct distribution of Golgi and endosomal markers. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG 6, and the BAG 6‐mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic control of Rab family small GTP ases through BAG 6

et al. 2019

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“…To date, 72 autosomal dominant mutations have been discovered in this gene, more than 30 of which are reported in ALS or FTD cases (including behavioral FTD, semantic dementia, and progressive non-fluent aphasia) (Al-Obeidi et al, 2018;Saracino et al, 2018;Bastola et al, 2019). Many of the reported VCP mutations are located on exon five within the N-terminal CDC48 domain, which is involved in ubiquitinbinding, meaning that mutations in this region may negatively affect the ubiquitin protein degradation pathway (Ganji et al, 2018;Twomey et al, 2019).…”

Section: Valosin Containing Protein (Vcp)mentioning

confidence: 99%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.

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“…Like other chaperones, it plays an important role in triaging its substrates. While its folding capability is minor, BAG-6 can act as a holdase and prevent aggregation of TA transmembrane proteins [210], and keep ERAD-substrates soluble before further processing by p97 [212,217].…”

Section: Degradation Through Bag-6mentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

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The VCP-UBXN1 Complex Mediates Triage of Ubiquitylated Cytosolic Proteins Bound to the BAG6 Complex

Cited by 29 publications

References 30 publications

Cytoplasmic control of Rab family small GTP ases through BAG 6

Cytoplasmic control of Rab family small GTP ases through BAG 6

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

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