Valosin-containing protein (VCP/p97) inhibition reduces viral clearance and induces toxicity associated with muscular damage

Oliva, Marta Del Rio; Basler, Michael

doi:10.1038/s41419-022-05461-w

Cited by 2 publications

(1 citation statement)

References 65 publications

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“…Mutations in the p97 gene have been associated with the development of multisystem proteinopathy (MSP) in humans, with the pathological accumulation of protein aggregates in the brain, muscle, and bone [ 25 , 26 , 27 , 28 ]. p97 has also been identified as a target for the treatment of cancer and neurological, viral, and parasitic diseases [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. p97 assembles as a homohexamer with a quaternary structure in the shape of a double-stacked ring in the absence of a substrate [ 14 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

Valimehr,

Vuillemot,

Kazemi

et al. 2024

IJMS

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Single-particle cryo-electron microscopy (cryo-EM) has been shown to be effective in defining the structure of macromolecules, including protein complexes. Complexes adopt different conformations and compositions to perform their biological functions. In cryo-EM, the protein complexes are observed in solution, enabling the recording of images of the protein in multiple conformations. Various methods exist for capturing the conformational variability through analysis of cryo-EM data. Here, we analyzed the conformational variability in the hexameric AAA + ATPase p97, a complex with a six-fold rotational symmetric core surrounded by six flexible N-domains. We compared the performance of discrete classification methods with our recently developed method, MDSPACE, which uses 3D-to-2D flexible fitting of an atomic structure to images based on molecular dynamics (MD) simulations. Our analysis detected a novel conformation adopted by approximately 2% of the particles in the dataset and determined that the N-domains of p97 sway by up to 60° around a central position. This study demonstrates the application of MDSPACE in analyzing the continuous conformational changes in partially symmetrical protein complexes, systems notoriously difficult to analyze due to the alignment errors caused by their partial symmetry.

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Section: Introductionmentioning

confidence: 99%

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

Valimehr,

Vuillemot,

Kazemi

et al. 2024

IJMS

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Cellular stress increases DRIP production and MHC Class I antigen presentation

Pach,

Basler

2024

Front. Immunol.

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BackgroundDefective ribosomal products (DRiPs) are non-functional proteins rapidly degraded during or after translation being an essential source for MHC class I ligands. DRiPs are characterized to derive from a substantial subset of nascent gene products that degrade more rapidly than their corresponding native retiree pool. So far, mass spectrometry analysis revealed that a large number of HLA class I peptides derive from DRiPs. However, a specific viral DRiP on protein level was not described. In this study, we aimed to characterize and identify DRiPs derived from a viral protein.MethodsUsing the nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) which is conjugated N–terminally to ubiquitin, or the ubiquitin-like modifiers FAT10 or ISG15 the occurrence of DRiPs was studied. The formation and degradation of DRiPs was monitored by western blot with the help of a FLAG tag. Flow cytometry and cytotoxic T cells were used to study antigen presentation.ResultsWe identified several short lived DRiPs derived from LCMV-NP. Of note, these DRiPs could only be observed when the LCMV–NP was modified with ubiquitin or ubiquitin-like modifiers, but not in the wild type form. Using proteasome inhibitors, we could show that degradation of LCMV-NP derived DRiPs were proteasome dependent. Interestingly, the synthesis of DRiPs could be enhanced when cells were stressed with the help of FCS starvation. An enhanced NP118–126 presentation was observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, or under FCS starvation.ConclusionTaken together, we visualize for the first time DRiPs derived from a viral protein. Furthermore, DRiPs formation, and therefore MHC-I presentation, is enhanced under cellular stress conditions. Our investigations on DRiPs in MHC class I antigen presentation open up new approaches for the development of vaccination strategies.

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Valosin-containing protein (VCP/p97) inhibition reduces viral clearance and induces toxicity associated with muscular damage

Cited by 2 publications

References 65 publications

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

Cellular stress increases DRIP production and MHC Class I antigen presentation

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