Extracellular vesicle‐mediated endothelial apoptosis and EV‐associated proteins correlate with COVID‐19 disease severity

Extracellular vesicles (EVs) play important roles in cell-cell communication. In budding yeast (Saccharomyces cerevisiae), EVs function as carriers to transport cargo proteins into the periplasm for storage during glucose starvation. However, intracellular organelles that synthesize these EV-associated cargo proteins have not been identified. Here, we investigated whether cytoplasmic organelles—called intracellular vesicle clusters (IVCs)—serve as sites for the synthesis of proteins targeted for secretion as EV-associated proteins. Using proteomics, we identified 377 IVC-associated proteins in yeast cells grown under steady-state low-glucose conditions, with the largest group being involved in protein translation. Isolated IVCs exhibited protein synthesis activities that required initiation and elongation factors. We have also identified 431 newly synthesized proteins on isolated IVCs. Expression of 103Q-GFP, a foreign protein with a long polyglutamine extension, resulted in distribution of this protein as large puncta that co-localized with IVC markers, including fructose-1,6-bisphosphatase (FBPase) and the vacuole import and degradation protein Vid24p. We did not observe this pattern in cycloheximide-treated cells or in cells lacking VID genes, required for IVC formation. The induction of 103Q-GFP on IVCs adversely affected total protein synthesis in intact cells and on isolated IVCs. This expression also decreased levels of EV-associated cargo proteins in the extracellular fraction without affecting the number of secreted EVs. Our results provide important insights into the functions of IVCs as sites for the synthesis of EV-associated proteins targeted for secretion to the periplasm.

Download Full-text

Extracellular Vesicles Hijack the Autophagic Pathway to Induce Tau Accumulation in Endolysosomes

10.1101/2020.05.27.118323 ◽

2020 ◽

Cited By ~ 2

Author(s):

Giona Pedrioli ◽

Marialuisa Barberis ◽

Maurizio Molinari ◽

Diego Morone ◽

Stéphanie Papin ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Model ◽

Extracellular Vesicle ◽

Clinical Progression ◽

Cargo Delivery ◽

Viable Solution ◽

Associated Proteins ◽

A Cell ◽

Acidic Compartment ◽

First Time

AbstractClinical progression of tauopathies is reflected by the transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles as transport vectors. However, the mechanism regulating extracellular vesicle cargo delivery to recipient cells is poorly understood. We established a cell model for investigating extracellular vesicle-delivery of membranes and proteins. In this model, extracellular vesicles are readily internalized and accumulate in endolysosomes. For the first time, we show that in this acidic compartment of recipient cells, extracellular vesicle-delivered Tau seeds cause the accumulation and abnormal folding of normal Tau by a process that requires the participation of autophagy. Endolysomes represent thus a cross-road where Tau seeds released from extracellular vesicles propagate on cellular Tau on its route for autophagy-mediated degradation, ultimately driving its accumulation, endolysosomal stress and cytotoxicity. Whilst, autophagy stimulation is considered as a viable solution to protect neurons from harmful cytosolic protein inclusions, our data suggest that this approach may favour the aberrant accumulation of neurodegeneration-associated proteins induced by exogenous pathogenic protein forms, with possible implications in the spreading of the disease.

Download Full-text

Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.01.002 ◽

2015 ◽

Vol 25 (3) ◽

pp. 231-237 ◽

Cited By ~ 6

Author(s):

J.C. van den Bergen ◽

B.H.A. Wokke ◽

M.A. Hulsker ◽

J.J.G.M. Verschuuren ◽

A.M. Aartsma-Rus

Keyword(s):

Muscular Dystrophy ◽

Disease Severity ◽

Becker Muscular Dystrophy ◽

Associated Proteins

Download Full-text

Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.03.009 ◽

2015 ◽

Vol 25 (6) ◽

pp. 530

Author(s):

C.A. Sewry

Keyword(s):

Muscular Dystrophy ◽

Disease Severity ◽

Becker Muscular Dystrophy ◽

Associated Proteins

Download Full-text

Sa1460 - Extracellular Vesicle C16 Ceramide and S1P Content in Alcoholic Hepatitis Correlates with Disease Severity and Resolution

Gastroenterology ◽

10.1016/s0016-5085(18)33727-2 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1120 ◽

Cited By ~ 2

Author(s):

Juan Pablo Arab ◽

Vikas Verma ◽

Rosa Martin-Mateos ◽

Douglas Simonetto ◽

Patrick S. Kamath ◽

...

Keyword(s):

Disease Severity ◽

Alcoholic Hepatitis ◽

Extracellular Vesicle

Download Full-text

Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus

Journal of Experimental Medicine ◽

10.1084/jem.20201138 ◽

2021 ◽

Vol 218 (5) ◽

Author(s):

Johannes Hartl ◽

Lee Serpas ◽

Yueyang Wang ◽

Ali Rashidfarrokhi ◽

Oriana A. Perez ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Severity ◽

Lupus Erythematosus ◽

Total Plasma ◽

Systemic Lupus ◽

Double Stranded Dna ◽

Free Dna ◽

Circulating Microparticles ◽

Associated Proteins

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.

Download Full-text

Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21155418 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5418 ◽

Cited By ~ 2

Author(s):

Song Yi Ko ◽

Honami Naora

Keyword(s):

Tumor Angiogenesis ◽

Therapy Resistance ◽

Extracellular Vesicle ◽

Biological Functions ◽

Vesicle Membrane ◽

Angiogenic Therapy ◽

Anti Cancer ◽

Associated Proteins ◽

Tumor Growth And Metastasis ◽

Prime Target

The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy.

Download Full-text

Basal Forebrain Deep Brain Stimulation Impacts the Regulation of Extracellular Vesicle Related Proteins in the Rat Brain

10.1101/374256 ◽

2018 ◽

Author(s):

Wenxue Li ◽

Laura Lozano Montes ◽

Jayakrishnan Nair ◽

Marta Dimanico ◽

Reza Mazloum ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Rat Brain ◽

Brain Stimulation ◽

Basal Forebrain ◽

Extracellular Vesicle ◽

Long Distance ◽

Therapeutic Benefits ◽

Neural Ensemble ◽

Associated Proteins ◽

Deep Brain

AbstractExtracellular vesicle (EV) signaling has attracted considerable attention in recent years because EVs play a key role in long distance cellular communication functions. EV studies have begun to reveal aspects of physiological and physiopathological regulation in numerous applications, although many areas remain to date largely unexplored. Deep brain stimulation (DBS) has shown remarkable therapeutic benefits of patients with neuropsychiatric disorders, but despite of the long and successful history of use, the mechanisms of action on neural ensemble activity are not yet fully understood. Here we explore how DBS of the basal forebrain impacts EV signaling in the rat brain. We employed differential centrifugations to isolate the EVs prefrontal cortex (PFC), hippocampus and striatum. We then performed quantitative analysis of EV-associated proteins using an MS-based proteomics method. We identified a considerable number of EV-associated proteins are modulated by DBS in three brain regions, some of which have been previously linked with central nervous system disorders. Particularly, neurofilament proteins NFL and NFM were both significantly changed in EVs of PFC, hippocampus and striatum after DBS stimulation compared with controls. The SOD1 protein, associated previously with neurodegenerative diseases, was significantly increased only in PFC. Our study is the first, to our knowledge, to use EV protein analysis to examine DBS effects on brain physiological regulation. Our findings open an entirely new perspective on brain area specific DBS effects.

Download Full-text

Extracellular Vesicle-Associated Proteins in Tissue Repair

Trends in Cell Biology ◽

10.1016/j.tcb.2020.09.009 ◽

2020 ◽

Vol 30 (12) ◽

pp. 990-1013

Author(s):

Marieke T. Roefs ◽

Joost P.G. Sluijter ◽

Pieter Vader

Keyword(s):

Tissue Repair ◽

Extracellular Vesicle ◽

Associated Proteins

Download Full-text