Does the protein UXT, which is a required for the NF-kB pathway, a substrate of the E3 ubiquitin-ligase SCF(Fbxo7)?

• Grant number: 17/07879-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2017
• End date: June 30, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Felipe Roberti Teixeira
• Grantee: Valentine Spagnol
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

The NF-kB signaling pathway control many cellular processes such as cellular proliferation, differentiation, apoptosis and immune response. One of the main components of this pathway is the UXT protein (Ubiquitously eXpressed Transcript), which is a component of the enhance some in the cell nuclei. Its knockdown inhibits the genes controlled by the NF-kB factor. Our research group in collaboration with the University of Cambridge/UK (Dr Heike Laman from Department of Pathology) identified UXT as a novel SCF(Fbxo7) potential substrate through the in vitro high throughput screening using the protein microarray as a source of substrates and the purified E3 ligase SCF(Fbxo7). It has been show in the past that Fbxo7 is an inhibitor of the NF-kB signaling pathway by ubiquitination of cIAP1 and TRAF2. Our preliminary results indicated that SCF(Fbxo7) interacts and polyubiquitinate the UXT protein though K63 and K48 ubiquitin chains. However, we still do not validate these results and neither evaluate the functional consequences of this modification in vivo in the presence and absence of the FBXO7. Furthermore, it was identified another isoform of UXT (UXT-V1) which is longer than the isoform 2 (UXT-V2) and more unstable, with reduced half life time. The UXT-V1 protect the cells from the apoptosis cell death by interaction with TRAF2, blocking the recruitment of FADD and caspase-8 for the TRAF2-RIP-TRAD complex. Thus, the aim of this proposal is evaluate the ubiquitination of both isoforms of UXT by the E3 ligase SCF(Fbxo7) and the functional consequences of this modification in terms of stability in the presence or absence of FBXO7. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DORES-SILVA, PAULO ROBERTO; RODRIGUES KIRALY, VANESSA THOMAZ; DE OLIVEIRA MORITZ, MILENE NOBREGA; BALASCO SERRAO, VITOR HUGO; SIQUEIRA DOS PASSOS, PATRICIA MARIA; SPAGNOL, VALENTINE; TEIXEIRA, FELIPE ROBERTI; GAVA, LISANDRA MARQUES; CAUVI, DAVID MARIO; INACIO RAMOS, CARLOS HENRIQUE; et al. New insights on human Hsp70-escort protein 1: Chaperone activity, interaction with liposomes, cellular localizations and HSPA's self-assemblies remodeling. International Journal of Biological Macromolecules, v. 182, p. 772-784, JUL 1 2021. (14/16646-0, 14/07206-6, 17/26131-5, 16/25798-3, 09/54216-9, 12/50161-8, 17/07879-9, 11/23110-0, 17/07335-9, 12/23730-1)

SPAGNOL, VALENTINE; OLIVEIRA, CAIO A. B.; RANDLE, SUZANNE J.; PASSOS, PATRICIA M. S.; CORREIA, CAMILA R. S. T. B.; SIMAROLI, NATALIA B.; OLIVEIRA, JOICE S.; MEVISSEN, TYCHO E. T.; MEDEIROS, ANA CARLA; GOMES, MARCELO D.; et al. The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1865, n. 1, JAN 2021. (16/25798-3, 16/21310-6, 16/00792-2, 17/22153-4, 17/07879-9, 18/09204-1, 19/03943-0, 18/01308-2)