Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification

Şentürk, Mümine; Lin, Guang; Zuo, Zhuang; Mao, Dongxue; Watson, Emma; Mikos, Antonios G.; Bellen, Hugo J.

doi:10.1038/s41556-019-0281-x

Cited by 109 publications

(107 citation statements)

References 64 publications

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“…Shi et al, 2018;Sullivan et al, 2016;Ugolino et al, 2016;Webster et al, 2016;Yang et al, 2016;Zhu et al, 2020), suggesting a mechanism whereby G4C2 repeats may have synergistically detrimental effects with haploinsufficient C9ORF72 in C9-ALS/FTD patients. Additionally, multiple forms of 15 familial ALS are caused by genes that regulate autophagy and lysosome function (Evans & Holzbaur, 2019;Lin et al, 2017;Ramesh & Pandey, 2017), and upregulation of lysosome function has been proposed to be beneficial in multiple preclinical models of ALS (Donde et al, 2020;Mao et al, 2019;Senturk et al, 2019;Y. Shi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

Cunningham

Zhang

Ruan

et al. 2020

Preprint

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Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which impaired NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified Ref(2)p/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.

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Section: Discussionmentioning

confidence: 99%

TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

Cunningham

Zhang

Ruan

et al. 2020

Preprint

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“…For instance, ubiquitin tagging is key in sorting protein substrates for either UPS-or autophagy-dependent degradation [84]. In this context, ubiquilin proteins (UBQLNs) bind the ubiquitin chains which are attached to a variety of aggregation-prone proteins, fostering their delivery and degradation by either UPS or autophagy [85][86][87]. Dysregulated UBQLNs are associated with an impaired protein degradation by both UPS and autophagy in models of neurodegeneration [88].…”

Section: Emerging Mechanisms Underlying Autophagy and Proteasome Crosmentioning

confidence: 99%

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

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Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

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“…While all UBQLN genes have a similar domain organization featuring UBL and UBA domains, many also contain unique motifs that could potentially confer client specificity or functional specialization. For example, UBQLN4 possesses a non-canonical LC3-binding motif (Lee et al, 2013) which is thought to confer a unique ability of the Ubqln family to promote autophagic protein degradation (N'Diaye et al, 2009a;2009b;Rothenberg et al, 2010;Şentürk et al, 2019). In addition, UBQLN2 contains a proline-rich repeat (the 'PXX-domain'), which may regulate client specificity (Gilpin et al, 2015), proteasome binding , and liquid-liquid phase separation into stress granules (Alexander et al, 2018;Dao et al, 2018;Sharkey et al, 2018). Mutations in UBQLN2 cause a heritable, X-linked, dominant form of ALS with frontotemporal dementia (fALS/FTD) in humans .…”

Section: Introductionmentioning

confidence: 99%

Global proteomics ofUbqln2-based murine models of ALS

Whiteley

Prado

Poot

et al. 2020

Preprint

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Familial forms of neurodegenerative diseases commonly involve mutation of aggregationprone proteins or components of the protein degradation machinery that act on aberrant proteins. Ubqln2 encodes a member of the UBL/UBA family of proteasome shuttle factors that is thought to facilitate proteasomal degradation of substrates, and mutation of this gene results in a familial form of ALS/FTD in humans. How Ubqln2 dysfunction leads to neurodegeneration, however, remains uncertain. We undertook a comprehensive study to identify proteomic changes upon Ubqln2 perturbation in multiple murine models of Ubqln2-mediated neurodegenerative disease. By performing quantitative multiplexed proteomics on neural tissues of affected animals, we identified a small group of proteins whose abundance is tightly linked to UBQLN2 function: the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Further studies using cultured cells of human origin, including induced neurons, found similar changes in protein abundance upon Ubqln2 loss, and pulse-chase studies suggested that PEG10 and TRIM32 are direct clients of UBQLN2. In conclusion, our study provides a deep understanding of the proteomic landscape of ALS-related Ubqln2 mutants and identifies candidate client proteins that are altered in vivo in disease models and whose degradation is promoted by UBQLN2.

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Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification

Cited by 109 publications

References 64 publications

TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Global proteomics ofUbqln2-based murine models of ALS

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