Autophagosome-Lysosome Fusion

Lőrincz, Péter; Juhász, Gábor

doi:10.1016/j.jmb.2019.10.028

Cited by 227 publications

(165 citation statements)

References 243 publications

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“…Both endosomal and lysosomal targeting are desirable for enhanced antigen presentation and CD4+ T-cell activation. 70,71 Lysosomes can fuse acidic autophagosomes, 72 facilitating protein processing; this has important implications for effective immune stimulation by modulation of MHC class II presentation. 62 We confirmed this desired effect by demonstrating that the T cells of previously infected SARS-CoV-2 patients more readily recognized N-ETSD than N. The findings of Gupta et al 71,73 and the data presented here strongly support the potential of enhanced efficacy of a vaccine construct specifically expressing the modified N-ETSD.…”

Section: Discussionmentioning

confidence: 99%

Th1 Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

Sieling

Zakin

Shin

et al. 2020

Preprint

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To address the need for a safe, efficacious vaccine against SARS-CoV-2 infection with the critical properties of enabling both blocking viral entry into cells and clearing virus from cells already infected, we have developed a bivalent, human adenovirus serotype 5 (hAd5) SARS-CoV-2 S-Fusion + N-ETSD vaccine that is currently in clinical testing. This vaccine uses the next-generation hAd5 [E1-, E2b-, E3-] platform previously used successfully in cancer patients with pre-existing adenovirus immunity, engineered to express both SARS-CoV-2 spike (S) protein modified to improve the generation of neutralizing antibodies to block entry of the virus, and nucleocapsid (N) protein with an Enhanced T cell Stimulation Domain (ETSD) to activate CD4+ and CD8+ T cells to clear the virus and block replication by killing infected cells. The targeting of N to endosomes and lysosomes to enhance CD4+ and CD8+ T-cell responses distinguishes our vaccine. In our previously reported pre-clinical studies we showed that in mice, the hAd5 S-Fusion + N-ETSD vaccine elicits both humoral and T-cell responses that are robust and T helper cell 1 (Th1) dominant. Here we report that the hAd5 S-Fusion + N-ETSD vaccine is recognized by anti-sera and T cells from previously SARS-CoV-2 infected patients, and that the presence of N is vital for T-cell recall. The findings presented herein: i. demonstrate specific recognition of hAd5 S-Fusion + N-ETSD infected cells by plasma antibodies from previously SARS-CoV-2 infected patients, but not antibodies from virus-naive subjects; ii. show enhanced binding of plasma SARS-CoV-2 antibodies from previously infected patients to monocyte-derived dendritic cells (MoDCs) expressing the hAd5 S-Fusion + N-ETSD vaccine as compared to hAd5 S-Fusion alone; iii. reveal N-ETSD localizes to vesicles associated with MHC class II antigen presentation, including endosomes, lysosomes, and autophagosomes in MoDCs; iv. demonstrate endosome/lysosome-targeted N-ETSD elicits higher interferon-gamma T-cell responses than cytoplasm-localized N; and v. N-ETSD alone or in the hAd5 S-Fusion + N-ETSD construct induces both CD4+ and CD8+ T cell memory recall. This recognition of hAd5 S-Fusion + N-ETSD vaccine antigens by T cells from previously SARS-CoV-2 infected patients, together with the ability of this vaccine candidate to elicit de novo immune responses in naive mice suggests that it re-capitulates the natural immune response to SARS-CoV-2 to activate both B and T cells towards viral neutralization and recognition of infected cells, critical for prevention of COVID-19 disease. Intriguingly, our hAd5 S-Fusion + N-ETSD T-cell biased vaccine has the potential to not only provide protection for uninfected individuals, but also to be utilized as a therapeutic for already infected patients to induce rapid clearance of the virus by activating T cells to kill the virus-infected cells, thereby reducing viral replication and lateral transmission.

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Section: Discussionmentioning

confidence: 99%

Th1 Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

Sieling

Zakin

Shin

et al. 2020

Preprint

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“…Autophagy is the cellular process for the degradation and recycling of the cellular material in certain metabolic circumstances [5]. During this pathway, autophagosomes fuse with lysosomes, where their engulfed substances are hydrolyzed by lysosomal enzymes [52]. The hydrolytic degradation of sugar-containing macromolecules, like polysaccharides, glycoproteins, and glycolipids, leads to monosaccharide formation in the lumen of autolysosomes [53].…”

Section: Processes Linked To Glucose Transport In the Organellesmentioning

confidence: 99%

Glucose Transport and Transporters in the Endomembranes

Lizák

Szarka

Kim

et al. 2019

IJMS

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Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose transporter) or SLC2A (Solute carrier 2A) families represent the main glucose transporters in mammalian cells, originally described as plasma membrane transporters. Glucose transport through intracellular membranes has not been elucidated yet; however, glucose is formed in the lumen of various organelles. The glucose-6-phosphatase system catalyzing the last common step of gluconeogenesis and glycogenolysis generates glucose within the lumen of the endoplasmic reticulum. Posttranslational processing of the oligosaccharide moiety of glycoproteins also results in intraluminal glucose formation in the endoplasmic reticulum (ER) and Golgi. Autophagic degradation of polysaccharides, glycoproteins, and glycolipids leads to glucose accumulation in lysosomes. Despite the obvious necessity, the mechanism of glucose transport and the molecular nature of mediating proteins in the endomembranes have been hardly elucidated for the last few years. However, recent studies revealed the intracellular localization and functional features of some glucose transporters; the aim of the present paper was to summarize the collected knowledge.

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“…Autophagy-related molecule expression is also increased in those animal muscles, including Bnip3, Beclin-1, and LC3II mRNAs, indicating that autophagosome–lysosome formation is accelerated in uremic skeletal tissue [ 98 , 99 ]. This fused structure forms autolysosomes, in which the sequestered cargos are degraded and recycled for the maintenance of cellular homeostasis [ 115 , 116 ]. Thus, it may promote skeletal muscle wasting in CKD [ 98 , 117 , 118 ].…”

Section: Experimental Laboratory Tools For Exploration Of Uremic Smentioning

confidence: 99%

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach

et al. 2020

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Sustained physical activity extends healthy life years while a lower activity due to sarcopenia can reduce them. Sarcopenia is defined as a decrease in skeletal muscle mass and strength due not only to aging, but also from a variety of debilitating chronic illnesses such as cancer and heart failure. Patients with chronic kidney disease (CKD), who tend to be cachexic and in frail health, may develop uremic sarcopenia or uremic myopathy due to an imbalance between muscle protein synthesis and catabolism. Here, we review clinical evidence indicating reduced physical activity as renal function deteriorates and explore evidence-supported therapeutic options focusing on nutrition and physical training. In addition, although sarcopenia is a clinical concept and difficult to recapitulate in basic research, several in vivo approaches have been attempted, such as rodent subtotal nephrectomy representing both renal dysfunction and muscle weakness. This review highlights molecular mechanisms and promising interventions for uremic sarcopenia that were revealed through basic research. Extensive study is still needed to cast light on the many aspects of locomotive organ impairments in CKD and explore the ways that diet and exercise therapies can improve both outcomes and quality of life at every level.

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Autophagosome-Lysosome Fusion

Cited by 227 publications

References 243 publications

Th1 Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

Th1 Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

Glucose Transport and Transporters in the Endomembranes

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach

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