Aggresome formation is regulated by RanBPM through an interaction with HDAC6

Salemi, Louisa M.; Almawi, A.W.; Lefebvre, Karen J.; Schild-Poulter, Caroline

doi:10.1242/bio.20147021

Cited by 29 publications

(30 citation statements)

References 81 publications

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“…Ran-binding protein-9 (RanBP9) levels have been found to be elevated in the AD patient brain [60]. It is proven that RanBP9 increases Aβ secretion by increasing the β-secretase activity [61], and it can also influence aggresome formation by interacting with HDAC6 [62]. However, there is no direct evidence elucidating HDAC6 and RanBP9 inter-relationship in Aβ aggresome formation and its autophagic degradation.…”

Section: Aggresomes In Admentioning

confidence: 99%

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati

Song

Tong

et al. 2020

Cells

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.

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Section: Aggresomes In Admentioning

confidence: 99%

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati

Song

Tong

et al. 2020

Cells

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“…To determine if RanBPM association with HDAC6 is necessary for its inhibition, we assayed levels of acetylated α-tubulin in RanBPM shRNA cells re-expressing either wildtype RanBPM or a RanBPM mutant bearing a LisH/CTLH domain deletion which we previously demonstrated impairs RanBPM’s association with HDAC6 [47]. We found that cells transfected with the LisH/CTLH (Δ360) RanBPM mutant had levels of acetylated α-tubulin similar to that of RanBPM shRNA cells and therefore was not able to restore acetylated α-tubulin to the same level as wildtype RanBPM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of HDAC6 activity through interaction with RanBPM and its associated CTLH complex

et al. 2017

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BackgroundHistone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase that promotes many cellular processes that lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) and HDAC6 and found that RanBPM expression inhibits HDAC6 activity. RanBPM is part of a putative E3 ubiquitin ligase complex, termed the C-terminal to LisH (CTLH) complex. Here, we investigated the involvement of the CTLH complex on HDAC6 inhibition and assessed the outcome of this regulation on the cellular motility induced by HDAC6.MethodsCell lines (Hela, HEK293 and immortalized mouse embryonic fibroblasts) stably or transiently downregulated for several components of the CTLH complex were employed for the assays used in this study. Interactions of HDAC6, RanBPM and muskelin were assessed by co-immunoprecipitations. Quantifications of western blot analyses were employed to evaluate acetylated α-tubulin levels. Confocal microscopy analyses were used to determine microtubule association of HDAC6 and CTLH complex members. Cell migration was evaluated using wound healing assays.ResultsWe demonstrate that RanBPM-mediated inhibition of HDAC6 is dependent on its association with HDAC6. We show that, while HDAC6 does not require RanBPM to associate with microtubules, RanBPM association with microtubules requires HDAC6. Additionally, we show that Twa1 (Two-hybrid-associated protein 1 with RanBPM) and MAEA (Macrophage Erythroblast Attacher), two CTLH complex members, also associate with α-tubulin and that muskelin, another component of the CTLH complex, is able to associate with HDAC6. Downregulation of CTLH complex members muskelin and Rmnd5A (Required for meiotic nuclear division homolog A) resulted in decreased acetylation of HDAC6 substrate α-tubulin. Finally, we demonstrate that the increased cell migration resulting from downregulation of RanBPM is due to the relief in inhibition of HDAC6 α-tubulin deacetylase activity.ConclusionsOur work shows that RanBPM, together with the CTLH complex, associates with HDAC6 and restricts cell migration through inhibition of HDAC6 activity. This study uncovers a novel function for the CTLH complex and suggests that it could have a tumour suppressive role in restricting HDAC6 oncogenic properties.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3430-2) contains supplementary material, which is available to authorized users.

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“…An important regulator of the aggresomal pathway is HDAC6, a member of class IIb histone deacetylases responsible for the homeostasis of the cellular MT apparatus [44]. Cells deficient in HDAC6 cannot form aggresomes [45,46]. HDAC6 is a key enzyme for clearing unubiquitinated proteins that fail to enter the proteasome pathway [47,48].…”

Section: Cellular Regulatory and Antiviral Effects Of Aggresomes And mentioning

confidence: 99%

Virus-Induced Cytoplasmic Aggregates and Inclusions Are Critical Cellular Regulatory and Antiviral Factors

Olasunkanmi

Chen

Mageto

et al. 2020

Viruses

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RNA granules, aggresomes, and autophagy are key players in the immune response to viral infections. They provide countermeasures that regulate translation and proteostasis in order to rewire cell signaling, prevent viral interference, and maintain cellular homeostasis. The formation of cellular aggregates and inclusions is one of the strategies to minimize viral infections and virus-induced cell damage and to promote cellular survival. However, viruses have developed several strategies to interfere with these cellular processes in order to achieve productive replication within the host cells. A review on how these mechanisms could function as modulators of cell signaling and antiviral factors will be instrumental in refining the current scientific knowledge and proposing means whereby cellular granules and aggregates could be induced or prevented to enhance the antiviral immune response in mammalian cells.

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Aggresome formation is regulated by RanBPM through an interaction with HDAC6

Cited by 29 publications

References 81 publications

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Inhibition of HDAC6 activity through interaction with RanBPM and its associated CTLH complex

Virus-Induced Cytoplasmic Aggregates and Inclusions Are Critical Cellular Regulatory and Antiviral Factors

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