HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6
Autor: | Luigina Romani, Maria Agnese Della-Fazia, Giuseppe Servillo, Marilena Castelli, Stefania Pieroni, Marina M. Bellet, Francesca Fallarino, Danilo Piobbico |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Cancer Research
Cell cycle checkpoint Cell division Immunology Regulator Article Cellular and Molecular Neuroscience Stress signalling Humans lcsh:QH573-671 Transcription factor Cell Nucleus Inflammation biology Chemistry lcsh:Cytology Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins NF-kappa B Transcription Factor RelA Membrane Proteins Cell Biology Epigenetics in immune cells Transmembrane protein Ubiquitin ligase Cell biology IκBα biology.protein Signal transduction Protein Binding Signal Transduction |
Zdroj: | Cell Death and Disease, Vol 11, Iss 10, Pp 1-14 (2020) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | HOPS/Tmub1 is a ubiquitously expressed transmembrane ubiquitin-like protein that shuttles between nucleus and cytoplasm during cell cycle progression. HOPS causes cell cycle arrest in G0/G1 phase, an event associated to stabilization of p19Arf, an important tumor suppressor protein. Moreover, HOPS plays an important role in driving centrosomal assembly and maintenance, mitotic spindle proper organization, and ultimately a correct cell division. Recently, HOPS has been described as an important regulator of p53, which acts as modifier, stabilizing p53 half-life and playing a key role in p53 mediating apoptosis after DNA damage. NF-κB is a transcription factor with a central role in many cellular events, including inflammation and apoptosis. Our experiments demonstrate that the transcriptional activity of the p65/RelA NF-κB subunit is regulated by HOPS. Importantly, Hops−/− cells have remarkable alterations of pro-inflammatory responses. Specifically, we found that HOPS enhances NF-κB activation leading to increase transcription of inflammatory mediators, through the reduction of IκBα stability. Notably, this effect is mediated by a direct HOPS binding to the E3 ubiquitin ligase TRAF6, which lessens TRAF6 stability ultimately leading increased IKK complex activation. These findings uncover a previously unidentified function of HOPS/Tmub1 as a novel modulator of TRAF6, regulating inflammatory responses driven by activation of the NF-κB signaling pathway. The comprehension on how HOPS/Tmub1 takes part to the inflammatory processes in vivo and whether this function is important in the control of proliferation and tumorigenesis could establish the basis for the development of novel pharmacological strategies. |
Databáze: | OpenAIRE |
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