The opposite role of two UBA–UBX containing proteins, p47 and SAKS1 in the degradation of a single ERAD substrate, α-TCR

Park, Eun Sil; Yoo, Yung Joon; Elangovan, Muthukumar

doi:10.1007/s11010-016-2860-5

Cited by 15 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The VCP adaptors UBXD8 and UBXD2 along with UFD1-NPL4 participate in ERAD (14)(15)(16). In contrast, UBXN1 was reported in two previous studies to be a negative regulator of ERAD (17,18). Nevertheless, we asked if UBXN1 is required for ERAD using well-established fluorescence reporter cell lines expressing membrane and luminal ER proteins: (i) green fluorescent protein-tagged T cell receptor ␣ (GFP-TCR␣), (ii) an alpha 1 antitrypsin null Hong Kong variant (A1AT NHK-GFP), and (iii) transthyretin D18G (TTR D18G-GFP).…”

Section: Resultsmentioning

confidence: 90%

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

Ganji

Mukkavalli

Somanji

et al. 2018

Molecular and Cellular Biology

View full text Add to dashboard Cite

A balance between protein synthesis and degradation is necessary to maintain cellular homeostasis. Failure to triage aberrant proteins may result in their accumulation and aggregation in the cytosol. The VCP-BAG6 complex facilitates a wide variety of ubiquitin-mediated quality control events at the ER; both prior to ER translocation as well as during ER associated degradation (ERAD). Yet, how ubiquitylated clients associated with BAG6 are recognized by VCP for proteasomal degradation is presently unknown. We have identified UBXN1 as the VCP adaptor in BAG6-dependent processes occurring prior to ER insertion but not during ERAD. Loss of VCP-UBXN1 results in the inappropriate stabilization of ubiquitylated BAG6 clients; their accumulation in insoluble aggregates and sensitizes cells to proteotoxic stress. Our results identify how VCP is specifically targeted to ubiquitylated substrates in the BAG6 triage pathway and suggest that degradation of ubiquitylated clients by the proteasome is reliant on UBXN1 association with ubiquitylated substrates and VCP catalytic activity.

show abstract

Section: Resultsmentioning

confidence: 90%

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

Ganji

Mukkavalli

Somanji

et al. 2018

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Among them, p47, Hsp70Ba and Hsp70Bb are highly induced in all Pex knockdowns, by which Hsp70Bb is induced by more than 6-fold in Pex1 RNAi . p47 is predicted to have ubiquitin binding activity and its human orthologue can interact with ubiquitinated substrates duWe utilized a previously developedring ERAD and are elevated upon ER stress 47 . Similarly, several ubiquitin ligase complex components are also up regulated, such as sip3 (HRD1 family) and Der-1.…”

Section: Resultsmentioning

confidence: 99%

Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Huang

Bai

2020

Preprint

View full text Add to dashboard Cite

Peroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result in severe brain, liver, kidney, and bone malfunctions. PBDs are due to mutations in peroxisome biogenesis factors (PEX genes) that are responsible for peroxisome assembly and function. There is increasing evidence suggesting that peroxisome import functions decline during aging. The transcriptome profiling of peroxisome import defects is still lacking. To identify conserved responses, we undertook a bioinformatic transcriptomic analysis on Drosophila oenocyte specific Pex1, Pex12 and Pex5 knockdowns. In addition, we performed analysis on human cells with induced peroxisome import stress. We uncovered that oenocyte-specific Pex1, Pex12 and Pex5 have distinct transcriptional profiles with each other. Using gene set enrichment analysis (GSEA), we identified protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is enriched and induced in all PEX knockdowns in Drosophila. Moreover, we uncovered decreased expression in ribosome biogenesis genes in flies and human cells. Indeed, we identified a stall at the 5’-ETS cleavage sites during the ribosome biogenesis and impaired 40S small ribosomal export in both flies and human. Our data indicates an unexpected link between peroxisome and ribosome biogenesis. Our results suggest that reduced ribosome biogenesis could be conserved cellular response to reduce peroxisome import stress.

show abstract

“…The adaptor SAKS1 plays a role in ERAD, where it has an inhibitory effect on the clearance of some ERAD substrates, for example α-TCR (T-cell receptor alpha) and NHK-HA (Null Hong Kong variant 1-antitrypsin) [ 94 , 95 ]. The protein recognizes both K48 ubiquitin chains and atypical K6 linked ubiquitin, which can be found on auto-ubiquitinated BRCA1 [ 94 , 96 ].…”

Section: P97 and Its Cofactorsmentioning

confidence: 99%

The AAA+ ATPase p97, a cellular multitool

Stach

Freemont

2017

Biochemical Journal

123

126

View full text Add to dashboard Cite

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

show abstract

The opposite role of two UBA–UBX containing proteins, p47 and SAKS1 in the degradation of a single ERAD substrate, α-TCR

Cited by 15 publications

References 19 publications

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

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

Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

The AAA+ ATPase p97, a cellular multitool

Contact Info

Product

Resources

About