The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase

Tarcan, Zeynep; Poovathumkadavil, Divyasree; Skagia, Aggeliki; Gambus, Agnieszka

doi:10.1016/j.jbc.2022.102234

Cited by 16 publications

(21 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This mechanism allows recognition of an unlimited number of targets while avoiding assembly of partial, inactive complexes. In agreement with our conclusions, the Labib and Gambus groups recently reported that Ubxn7 is the primary UBA-UBX protein that promotes CMG unloading in vertebrates 61,67 , and that Faf1 can partially substitute for Ubxn7 61 .…”

Section: Discussionsupporting

confidence: 93%

Cooperative assembly of p97 complexes involved in replication termination

et al. 2022

View full text Add to dashboard Cite

The p97 ATPase extracts polyubiquitylated proteins from diverse cellular structures in preparation for destruction by the proteasome. p97 functions with Ufd1-Npl4 and a variety of UBA-UBX co-factors, but how p97 complexes assemble on ubiquitylated substrates is unclear. To address this, we investigated how p97 disassembles the CMG helicase after it is ubiquitylated during replication termination. We show that p97Ufd1-Npl4 recruitment to CMG requires the UBA-UBX protein Ubxn7, and conversely, stable Ubxn7 binding to CMG requires p97Ufd1-Npl4. This cooperative assembly involves interactions between Ubxn7, p97, Ufd1-Npl4, and ubiquitin. Another p97 co-factor, Faf1, partially compensates for the loss of Ubxn7. Surprisingly, p97Ufd1-Npl4-Ubxn7 and p97Ufd1-Npl4-Faf1 also assemble cooperatively on unanchored ubiquitin chains. We propose that cooperative and substrate-independent recognition of ubiquitin chains allows p97 to recognize an unlimited number of polyubiquitylated proteins while avoiding the formation of partial, inactive complexes.

show abstract

Section: Discussionsupporting

confidence: 93%

Cooperative assembly of p97 complexes involved in replication termination

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Our results likely apply to higher eukaryotes, as a general role for the mammalian Rad23 homologs HR23A and HR23B in proteasomal protein degradation has been well established (Yokoi and Hanaoka, 2017), and the Ubx5 homolog Ubxn7 is involved in the degradation of several proteins, including HIF1α, NRF2, and components of the DNA replication machinery (Alexandru et al, 2008; Di Gregorio et al, 2021; Tarcan et al, 2022). The role of the mammalian Shp1 homologs p47 and p37 is less clear, as they have been implicated mostly in the ubiquitin-independent disassembly of protein complexes by the p97 ATPase (Kracht et al, 2020; van den Boom et al, 2021; Weith et al, 2018).…”

Section: Discussionmentioning

confidence: 70%

Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation

Li,

Ji,

Paulo

et al. 2023

Preprint

View full text Add to dashboard Cite

SUMMARYMost eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex, rather than substrate recruitment.In vivoexperiments confirm that many proteins undergo bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase before being degraded.

show abstract

“…Crucially, UBXN7 assists p97-Ufd1-Npl4-mediated extraction of the helicase ( Sonneville et al, 2017 ; Xia et al, 2021 ; Kochenova et al, 2022 ). FAF1 can compensate for UBXN7, although this is controversial ( Fujisawa et al, 2022 ; Tarcan et al, 2022 ).…”

Section: Two Alternative Pathways Of Targeting Through Distinct Adaptersmentioning

confidence: 99%

Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine

Meyer

Boom²

2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

The AAA+ ATPase p97 (also called VCP or Cdc48) is a major protein unfolding machine with hundreds of clients in diverse cellular pathways that are critical for cell homeostasis, proliferation and signaling. In this review, we summarize recent advances in understanding how diverse client proteins are targeted to the p97 machine to facilitate client degradation or to strip clients from binding partners for regulation. We describe an elaborate system that is governed by at least two types of alternative adapters. The Ufd1-Npl4 adapter along with accessory adapters targets ubiquitylated clients in the majority of pathways and uses ubiquitin as a universal unfolding tag. In contrast, the family of SEP-domain adapters such as p37 can target clients directly to p97 in a ubiquitin-independent manner. Despite the different targeting strategies, both pathways converge by inserting the client into the p97 pore to initiate a peptide threading mechanism through the central channel of p97 that drives client protein unfolding, protein extraction from membranes and protein complex disassembly processes.

show abstract

The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase

Cited by 16 publications

References 46 publications

Cooperative assembly of p97 complexes involved in replication termination

Cooperative assembly of p97 complexes involved in replication termination

Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation

Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine

Contact Info

Product

Resources

About