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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway

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Spagnol, Valentine [1] ; Oliveira, Caio A. B. [1] ; Randle, Suzanne J. [2] ; Passos, Patricia M. S. [1] ; Correia, Camila R. S. T. B. [1] ; Simaroli, Natalia B. [1] ; Oliveira, Joice S. [1] ; Mevissen, Tycho E. T. [3, 4] ; Medeiros, Ana Carla [5] ; Gomes, Marcelo D. [5] ; Komander, David [3, 6] ; Laman, Heike [2] ; Teixeira, Felipe Roberti [1]
Total Authors: 13
Affiliation:
[1] Univ Fed Sao Carlos, Dept Genet & Evolut, Rod Washington Luis, Km 235, BR-13565905 Sao Carlos - Brazil
[2] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP - England
[3] MRC Lab Mol Biol, Francis Crick Ave, Cambridge Biomed Campus, Cambridge CB2 0QH - England
[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave, Boston, MA 02115 - USA
[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Sao Paulo - Brazil
[6] Walter & Eliza Hall Inst Med Res, Ubiquitin Signalling Div, 1G Royal Parade, Parkville, Vic 3052 - Australia
Total Affiliations: 6
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1865, n. 1 JAN 2021.
Web of Science Citations: 0
Abstract

Background: Ubiquitously eXpressed Transcript isoform 2 (UXT-V2) is a prefoldin-like protein involved in NF-kappa B signaling, apoptosis, and the androgen and estrogen response. UXT-V2 is a cofactor in the NF-kappa B transcriptional enhanceosome, and its knockdown inhibits TNF-alpha -induced NF-kappa B activation. Fbxo7 is an F-box protein that interacts with SKP1, Cullin1 and RBX1 proteins to form an SCF(Fbxo7) E3 ubiquitin ligase complex. Fbxo7 negatively regulates NF-kappa B signaling through TRAF2 and cIAP1 ubiquitination. Methods: We combine co-immunoprecipitation, ubiquitination in vitro and in vivo, cycloheximide chase assay, ubiquitin chain restriction analysis and microscopy to investigate interaction between Fbxo7 and overexpressed UXT-V2-HA. Results: The Ub1 domain of Fbxo7 contributes to interaction with UXT-V2. This substrate is polyubiquitinated by SCF(Fbxo7) with K48 and K63 ubiquitin chain linkages in vitro and in vivo. This post-translational modification decreases UXT-V2 stability and promotes its proteasomal degradation. We further show that UXT-V1, an alternatively spliced isoform of UXT, containing 12 additional amino acids at the N-terminus as compared to UXT-V2, also interacts with and is ubiquitinated by Fbxo7. Moreover, FBXO7 knockdown promotes UXT-V2 accumulation, and the overexpression of Fbxo7-Delta F-box protects UXT-V2 from proteasomal degradation and enhances the responsiveness of NF-kappa B reporter. We find that UXT-V2 colocalizes with Fbxo7 in the cell nucleus. Conclusions: Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-kappa B signaling pathway. General significance: Discovering new substrates of E3 ubiquitin-ligase SCF(Fbxo7) contributes to understand its function in different diseases such as cancer and Parkinson. (AU)

FAPESP's process: 16/25798-3 - Functional consequences of rearrangements to the FBXL17 gene detected in patient samples and cancer cell lines, on the E3 ubiquitin-ligase SCF(Fbxl17) activity
Grantee:Felipe Roberti Teixeira
Support type: Regular Research Grants
FAPESP's process: 16/21310-6 - Regulations mechanisms of the Wnt signalling pathway by E3 ubiquitin ligase SCF(Fbxo7)
Grantee:Caio Almeida Batista de Oliveira
Support type: Scholarships in Brazil - Master
FAPESP's process: 16/00792-2 - Functional characterization of the E3 ubiquitin-ligase SCF(Fbxo7/PARK15) in the oncogenic Wnt pathway and mitochondrial homeostasis
Grantee:Felipe Roberti Teixeira
Support type: Regular Research Grants
FAPESP's process: 17/22153-4 - Identification of the ubiquitination sites in mitochondrial protein TOMM20 modified by the E3 ubiquitin-ligase SCF(Fbxo7)
Grantee:Natália Borges Simaroli
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 17/07879-9 - Does the protein UXT, which is a required for the NF-kB pathway, a substrate of the E3 ubiquitin-ligase SCF(Fbxo7)?
Grantee:Valentine Spagnol
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 18/09204-1 - Functional consequences of truncations in the Fbxl17 gene on the stability and activity of E3 ubiquitin ligase SCF (Fbx17)
Grantee:Joice Silva de Oliveira
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 19/03943-0 - Cloning of Fbxl17 domains in bacterial expression vectors
Grantee:Camila Rolemberg Santana Travaglini Berti de Correia
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 18/01308-2 - Genes Differentially Expressed During Reversion Skeletal Muscle Atrophy
Grantee:Marcelo Damário Gomes
Support type: Regular Research Grants