HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53‐dependent mitochondrial apoptosis

Castelli, Marilena; Piobbico, Danilo; Chiacchiaretta, Martina; Brunacci, Cinzia; Pieroni, Stefania; Bartoli, D.; Gargaro, Marco; Fallarino, Francesca; Puccetti, Paolo; Soddu, Silvia; Fazia, Maria Agnese Della; Servillo, Giuseppe

doi:10.15252/embr.201948073

Cited by 23 publications

(38 citation statements)

References 63 publications

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“…HOPS has been shown to interact with the tumor suppressors p19 Arf enabling its stabilization through the involvement of the nucleolar protein nucleophosmin (NPM) 14 . Recently, HOPS has been reported to be a fundamental regulator of mitochondrial p53 activity during DNA damage-induced apoptosis 15 . HOPS is abundantly expressed in the brain, where it plays a role in the regulation of basal synaptic transmission 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

et al. 2020

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“…We can speculate that HOPS localisation in nucleus and the differentiation of lens cells are accompanied by a progressive arrest of proliferation, which triggers the differentiation. Recently, we demonstrated that HOPS UBL plays a notable role, as protein modifier, regulating p53 stability and triggering the p53-mediated apoptosis [ 5 ]. In such a complex structure as lens is the role of protein modifiers and ubiquitin is fundamental and the machinery involved in proteasomal pathway execution is strategic in the shift from proliferation to differentiation [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…HOPS is involved in p53 stabilisation, p53-mediated mitochondrial apoptosis and p53 nuclear import. This evidence suggests that HOPS acts as potential tumour suppressor by its ubiquitin-like domain [ 5–7 ].…”

Section: Introductionmentioning

confidence: 99%

Functional expression and localisation of HOPS/TMUB1 in mouse lens

et al. 2021

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Transparency represents the functional phenotype of eye lens. A number of defined steps including quiescence, proliferation, migration and cell differentiation culminates in cell elongation and organelle degradation, allowing the light to reach the retina. HOPS/TMUB1 is a nucleo-cytoplasmic shuttling protein, highly expressed both in vivo and in vitro proliferating systems, bearing an ubiquitin-like domain. The present study shows HOPS expression during the phases of lens cell proliferation and fiber differentiation, and its localization in lens compartments. In lens, HOPS localizes mainly in the nucleus of central epithelial cells. During mitosis HOPS/TMUB1 shuttles to the cytoplasm and returns in the nucleus at the end of mitosis. The differentiating cells share distinct HOPS/TMUB1 localization in transitional zone depending on the differentiation phases. HOPS/TMUB1 is observed in lens cortex and nucleus. Here, it is attached to fibers, having a structural function with crystallin proteins, probably acting in the ubiquitin-proteasome system.

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“…( A ) Phylogeny of ubiquitin (Ub), ubiquitin-like proteins (UBLs) and Ub/UBL domains fused to human proteins. Genome stability associations are highlighted in green and apply to the following in addition to ISG15: Ub [ 3 , 10 ], Parkin [ 47 , 48 , 49 , 50 ], NEDD8 [ 11 ], UBTD1 [ 51 ], FAT10 [ 12 ], SF3A1 [ 52 ], RAD23A and RAD23B [ 53 ], TMUB1 (aka HOPS) [ 54 , 55 , 56 ], UBL5 (aka HUB1) [ 12 ], UHRF1 [ 57 , 58 , 59 ], ELOB (aka TCEB2) [ 60 ], USP48 [ 61 , 62 ], ATG12 [ 63 ], BAG6 [ 64 ], RBCK1 [ 65 ], BAG1 [ 66 , 67 ], HERPUD1 [ 68 ], UFM1 [ 12 ], UBQLN4 [ 69 ], SUMO1, SUMO2 and SUMO3 [ 70 ]; sequence similarity to ubiquitin is highlighted in the outermost ring ranging from GABARAP (9.59%) in red over a white midpoint to NEDD8 (58%) in blue. Ub/UBL domains are limited to curated UniProt entries.…”

Section: Isg15 and Isgylationmentioning

confidence: 99%

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

2020

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Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.

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HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53‐dependent mitochondrial apoptosis

Cited by 23 publications

References 63 publications

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6

Functional expression and localisation of HOPS/TMUB1 in mouse lens

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

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