SUMO enhances unfolding of SUMO–polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex

Lee, Hyein G; Lemmon, Abigail; Lima, Christopher D.

doi:10.1073/pnas.2213703120

Cited by 6 publications

(4 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SUMOylation is also directly linked to protein degradation as it can act as a signal for ATPases such as Cdc48 that target SUMOylated proteins for degradation 50 . Moreover, SUMOylation can serve as a platform for StUbLs that can ubiquitinate SUMOylated proteins for degradation 37 , 51 .…”

Section: Resultsmentioning

confidence: 99%

Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2

Kumar,

Mathew,

Stirling

2024

Nat Commun

View full text Add to dashboard Cite

Spatial compartmentalization is a key facet of protein quality control that serves to store disassembled or non-native proteins until triage to the refolding or degradation machinery can occur in a regulated manner. Yeast cells sequester nuclear proteins at intranuclear quality control bodies (INQ) in response to various stresses, although the regulation of this process remains poorly understood. Here we reveal the SUMO modification of the small heat shock protein Btn2 under DNA damage and place Btn2 SUMOylation in a pathway promoting protein clearance from INQ structures. Along with other chaperones, and degradation machinery, Btn2-SUMO promotes INQ clearance from cells recovering from genotoxic stress. These data link small heat shock protein post-translational modification to the regulation of protein sequestration in the yeast nucleus.

show abstract

Section: Resultsmentioning

confidence: 99%

Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2

Kumar,

Mathew,

Stirling

2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Since our mass photometry analysis suggested a stoichiometry of 2-3 bound VCF1 molecules per p97 hexamer (Fig. 4a), we used AlphaFold-Multimer prediction to generate a model of a UFD1-NPL4-bound p97 hexamer that agrees with experimentally determined structures [30][31][32] and superimposed three VCF1 VRM-containing helices onto this model (Supplementary Fig. 4h, i).…”

Section: Vcf1 and Ufd1-npl4 Form A Joint Complex With P97mentioning

confidence: 99%

VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates

Mirsanaye,

Hoffmann,

Weisser

et al. 2024

Nat Commun

View full text Add to dashboard Cite

The hexameric AAA+ ATPase p97/VCP functions as an essential mediator of ubiquitin-dependent cellular processes, extracting ubiquitylated proteins from macromolecular complexes or membranes by catalyzing their unfolding. p97 is directed to ubiquitylated client proteins via multiple cofactors, most of which interact with the p97 N-domain. Here, we discover that FAM104A, a protein of unknown function also named VCF1 (VCP/p97 nuclear Cofactor Family member 1), acts as a p97 cofactor in human cells. Detailed structure-function studies reveal that VCF1 directly binds p97 via a conserved α-helical motif that recognizes the p97 N-domain with unusually high affinity, exceeding that of other cofactors. We show that VCF1 engages in joint p97 complex formation with the heterodimeric primary p97 cofactor UFD1-NPL4 and promotes p97-UFD1-NPL4-dependent proteasomal degradation of ubiquitylated substrates in cells. Mechanistically, VCF1 indirectly stimulates UFD1-NPL4 interactions with ubiquitin conjugates via its binding to p97 but has no intrinsic affinity for ubiquitin. Collectively, our findings establish VCF1 as an unconventional p97 cofactor that promotes p97-dependent protein turnover by facilitating p97-UFD1-NPL4 recruitment to ubiquitylated targets.

show abstract

“…Further work should also include examining the host of p97 interacting proteins for activities that assist client targeting or even serve as novel client adapters. Likewise, we need to understand how targeting is regulated, for example through posttranslational modifications other than ubiquitylation including phosphorylation or SUMOylation ( Lee et al, 2023 ). With powerful biochemical unfolding and disassembly assays at hand, there is no excuse to not validate and dissect these activities mechanistically in vitro .…”

Section: Conclusion Remarks and Perspectivementioning

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

SUMO enhances unfolding of SUMO–polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex

Cited by 6 publications

References 65 publications

Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2

Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2

VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates

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

Contact Info

Product

Resources

About