scholarly journals Cdc48 and ubiquilins confer selective anterograde protein sorting and entry into the multivesicular body in yeast

2018 ◽  
Vol 29 (8) ◽  
pp. 948-963 ◽  
Author(s):  
Rachel Kama ◽  
Galina Gabriely ◽  
Vydehi Kanneganti ◽  
Jeffrey E. Gerst
Keyword(s):  
Protein Sorting ◽  
Multivesicular Body ◽  
Linkage Groups ◽  
Disease Pathogenesis ◽  
Proteolytic Activation ◽  
Ubiquitinated Proteins ◽  
Independent Functions ◽  
Specific Proteins ◽  
Lateral Sclerosis ◽  
Human Neurodegenerative Disease

Cdc48/p97 is known primarily for the retrotranslocation of misfolded proteins in endoplasmic reticulum (ER)-associated protein degradation (ERAD). Here we uncover a novel function for both Cdc48 and the conserved ubiquitin-associated/ubiquitin-like ubiquitin receptor (ubiquilin) proteins in yeast (e.g., Ddi1, Dsk2, and Rad23), which deliver ubiquitinated proteins to the proteasome for degradation. We show that Cdc48, its core adaptors Npl4 and Ufd1, and the ubiquilins confer the constitutive anterograde delivery of carboxypeptidase S (Cps1), a membranal hydrolase, to the multivesicular body (MVB) and vacuolar lumen. Cdc48 and Ddi1 act downstream of Rsp5-dependent Cps1 ubiquitination to facilitate the disassembly of insoluble Cps1 oligomers and upstream of ESCRT-0 to facilitate the entry of soluble protein into the MVB. Consequentially, detergent-insoluble Cps1 accumulates in cells bearing mutations in CDC48, DDI1, and all three ubiquilins (ddi1Δ, dsk2Δ, rad23Δ). Thus, Cdc48 and the ubiquilins have ERAD- and proteasome-independent functions in the anterograde delivery of specific proteins to the yeast vacuole for proteolytic activation. As Cdc48/p97 and the ubiquilins are major linkage groups associated with the onset of human neurodegenerative disease (e.g., amytrophic lateral sclerosis, Alzheimer’s, and Paget’s disease of the bone), there may be a connection between their involvement in anterograde protein sorting and disease pathogenesis.

scholarly journals Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease

2007 ◽  
Vol 179 (3) ◽  
pp. 485-500 ◽  
Author(s):  
Maria Filimonenko ◽  
Susanne Stuffers ◽  
Camilla Raiborg ◽  
Ai Yamamoto ◽  
Lene Malerød ◽  
...  
Keyword(s):  
Multivesicular Body ◽  
Protein Aggregates ◽  
Multivesicular Bodies ◽  
Ubiquitinated Protein ◽  
Endosomal Sorting ◽  
Ubiquitinated Proteins ◽  
Protein Deposits ◽  
Autophagic Degradation ◽  
Lateral Sclerosis ◽  
In Cells

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

scholarly journals Human ESCRT-II Complex and Its Role in Human Immunodeficiency Virus Type 1 Release

2006 ◽  
Vol 80 (19) ◽  
pp. 9465-9480 ◽  
Author(s):  
Charles Langelier ◽  
Uta K. von Schwedler ◽  
Robert D. Fisher ◽  
Ivana De Domenico ◽  
Paul L. White ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Protein Sorting ◽  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Vesicle Formation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The budding of many enveloped RNA viruses, including human immunodeficiency virus type 1 (HIV-1), requires some of the same cellular machinery as vesicle formation at the multivesicular body (MVB). In Saccharomyces cerevisiae, the ESCRT-II complex performs a central role in MVB protein sorting and vesicle formation, as it is recruited by the upstream ESCRT-I complex and nucleates assembly of the downstream ESCRT-III complex. Here, we report that the three subunits of human ESCRT-II, EAP20, EAP30, and EAP45, have a number of properties in common with their yeast orthologs. Specifically, EAP45 bound ubiquitin via its N-terminal GRAM-like ubiquitin-binding in EAP45 (GLUE) domain, both EAP45 and EAP30 bound the C-terminal domain of TSG101/ESCRT-I, and EAP20 bound the N-terminal half of CHMP6/ESCRT-III. Consistent with its expected role in MVB vesicle formation, (i) human ESCRT-II localized to endosomal membranes in a VPS4-dependent fashion and (ii) depletion of EAP20/ESCRT-II and CHMP6/ESCRT-III inhibited lysosomal targeting and downregulation of the epidermal growth factor receptor, albeit to a lesser extent than depletion of TSG101/ESCRT-I. Nevertheless, HIV-1 release and infectivity were not reduced by efficient small interfering RNA depletion of EAP20/ESCRT-II or CHMP6/ESCRT-III. These observations indicate that there are probably multiple pathways for protein sorting/MVB vesicle formation in human cells and that HIV-1 does not utilize an ESCRT-II-dependent pathway to leave the cell.

scholarly journals Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond

2009 ◽  
Vol 187 (6) ◽  
pp. 761-772 ◽  
Author(s):  
Hristelina Ilieva ◽  
Magdalini Polymenidou ◽  
Don W. Cleveland
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorders ◽  
Cell Types ◽  
Neuronal Dysfunction ◽  
Inherited Disease ◽  
Supporting Cells ◽  
Cerebellar Ataxias ◽  
Multiple Cell ◽  
Lateral Sclerosis ◽  
Human Neurodegenerative Disease

Selective degeneration and death of one or more classes of neurons is the defining feature of human neurodegenerative disease. Although traditionally viewed as diseases mainly affecting the most vulnerable neurons, in most instances of inherited disease the causative genes are widely—usually ubiquitously—expressed. Focusing on amyotrophic lateral sclerosis (ALS), especially disease caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1), we review here the evidence that it is the convergence of damage developed within multiple cell types, including within neighboring nonneuronal supporting cells, which is crucial to neuronal dysfunction. Damage to a specific set of key partner cells as well as to vulnerable neurons may account for the selective susceptibility of neuronal subtypes in many human neurodegenerative diseases, including Huntington's disease (HD), Parkinson's disease (PD), prion disease, the spinal cerebellar ataxias (SCAs), and Alzheimer's disease (AD).

One Ubiquitin, Two Ubiquitin, Three Ubiquitin, Four

2007 ◽  
Vol 2007 (369) ◽  
pp. tw26-tw26
Author(s):  
Stella M. Hurtley
Keyword(s):  
Protein Degradation ◽  
Full Text ◽  
Intracellular Signaling ◽  
Protein Sorting ◽  
Link Type ◽  
Protein Ubiquitination ◽  
Independent Functions ◽  
Cellular Pathways

The role of protein ubiquitination is well known in promoting regulated protein degradation. Mukhopadhyay and Riezman review what is known about the contribution of protein ubiquitination in other cellular pathways, including intracellular signaling, endocytosis, and protein sorting.D. Mukhopadhyay, H. Riezman, Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science315, 201-205 (2007). [Abstract][Full Text]

scholarly journals Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach

2020 ◽  
Vol 21 (9) ◽  
pp. 3243 ◽  
Author(s):  
Matteo Bordoni ◽  
Eveljn Scarian ◽  
Federica Rey ◽  
Stella Gagliardi ◽  
Stephana Carelli ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Therapeutic Approach ◽  
Disease Pathogenesis ◽  
Self Assembling ◽  
Promising Therapeutic Approach ◽  
Cord Injury ◽  
Different Types ◽  
Supporting Material ◽  
Carbon Based Nanomaterials ◽  
Lateral Sclerosis

Neurodegenerative disorders (i.e., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and spinal cord injury) represent a great problem worldwide and are becoming prevalent because of the increasing average age of the population. Despite many studies having focused on their etiopathology, the exact cause of these diseases is still unknown and until now, there are only symptomatic treatments. Biomaterials have become important not only for the study of disease pathogenesis, but also for their application in regenerative medicine. The great advantages provided by biomaterials are their ability to mimic the environment of the extracellular matrix and to allow the growth of different types of cells. Biomaterials can be used as supporting material for cell proliferation to be transplanted and as vectors to deliver many active molecules for the treatments of neurodegenerative disorders. In this review, we aim to report the potentiality of biomaterials (i.e., hydrogels, nanoparticles, self-assembling peptides, nanofibers and carbon-based nanomaterials) by analyzing their use in the regeneration of neural and glial cells their role in axon outgrowth. Although further studies are needed for their use in humans, the promising results obtained by several groups leads us to suppose that biomaterials represent a potential therapeutic approach for the treatments of neurodegenerative disorders.

ESCRTs and human disease

2009 ◽  
Vol 37 (1) ◽  
pp. 167-172 ◽  
Author(s):  
Suraj Saksena ◽  
Scott D. Emr
Keyword(s):  
Human Disease ◽  
Protein Sorting ◽  
Critical Role ◽  
Multivesicular Body ◽  
Human Diseases ◽  
Down Regulation ◽  
Endosomal Sorting ◽  
Retroviral Budding

The ESCRT (endosomal sorting complex required for transport) machinery plays a critical role in receptor down-regulation, retroviral budding, and other normal and pathological processes. The ESCRT components are conserved in all five major subgroups of eukaryotes. This review summarizes the growing number of links identified between ESCRT-mediated protein sorting in the MVB (multivesicular body) pathway and various human diseases.

scholarly journals Caspar, an adapter for VAP and TER94, delays the progression of disease by regulating glial inflammation in a Drosophila model of ALS8

2021 ◽  
Author(s):  
Shweta Tendulkar ◽  
Sushmitha Hegde ◽  
Aparna Thulasidharan ◽  
Lovleen Garg ◽  
Bhagyashree Kaduskar ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Motor Dysfunction ◽  
Ubiquitinated Proteins ◽  
Drosophila Model ◽  
Progression Of Disease ◽  
Uba Domain ◽  
Strong Candidate ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal, late-onset, progressive motor neurodegenerative disorder. We have been studying cellular and molecular mechanisms involved in ALS using a vesicle-associated membrane protein-associated protein B (VAPB/ALS8) Drosophila model, which mimics many systemic aspects of the human disease. Here, we show that the ER-resident VAPB interacts with Caspar, an ortholog of human fas associated factor 1 (FAF1). Caspar, in turn, interacts with transitional endoplasmic reticulum ATPase (TER94), a fly ortholog of ALS14 (VCP/p97, Valosin-containing protein), via its UBX domain and poly-ubiquitinated proteins with its UBA domain. Caspar overexpression in the glia extends lifespan and also slows the progression of motor dysfunction in the ALS8 model, a phenomenon that we ascribe to its ability to restrain age-dependant inflammation, modulated by Relish/NFBκ signaling. We hypothesize that Caspar is a key molecule in the pathogenesis of ALS. Caspar connects the plasma membrane (PM) localized immune signalosome to the ER-based VAPB degradative machinery, presumably at PM:ER contact sites. The Caspar:TER94:VAPB complex appears to be a strong candidate for regulating both protein homeostasis and NFκ signaling. These, in turn, regulate glial inflammation and determine the progression of the disease. Our study projects human FAF1 as an important protein target to alleviate the progression of motor neuron disease.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kathleen M Cunningham ◽  
Kirstin Maulding ◽  
Kai Ruan ◽  
Mumine Senturk ◽  
Jonathan C Grima ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Import ◽  
Transcriptional Regulator ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
Disease Pathogenesis ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted 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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