LAMP2A regulates the loading of proteins into exosomes

Ferreira, João Vasco; Soares, Amílcar; Ramalho, José S.; Carvalho, Catarina Máximo; Cardoso, Helena; Pintado, Petra; Carvalho, Ana Sofía; Beck, Hans Christian; Matthiesen, Rune; Zuzarte, Mónica; Girão, Henrique; Niel, Guillaume van; Pereira, Paulo

doi:10.1126/sciadv.abm1140

Cited by 97 publications

(73 citation statements)

References 59 publications

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“…The availability of cost-effective large-scale production, isolation, and characterization methods of exosomes are already being explored [ 186 , 189 ]. A growing number of new analytical techniques promise to provide new insights into the uniqueness of exosomes and may stimulate the development of the next generation of modified MSC-exosomes [ 190 ].…”

Section: Discussionmentioning

confidence: 99%

Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

Chen

Sun

Qian

et al. 2022

Stem Cells International

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Mesenchymal stem cells (MSCs) have been widely applied to regenerative medicine owing to their multiple differentiation, self-renewal, and immunomodulatory abilities. Exosomes are cell-secreted natural nanovesicles and thought to be mediators of intercellular communication and material transport. The therapeutic potential of MSCs can be largely attributed to MSC-derived exosomes (MSC-exosomes). Emerging evidence suggests that the therapeutic efficacy of MSC-exosomes is highly dependent on the status of MSCs, and optimization of the extracellular environment affects the exosomal content. Pretreatment methods including three-dimensional cultures, hypoxia, and other biochemical cues have been shown to potentially enhance the biological activity of MSC-exosomes while maintaining or enhancing their production. On the other hand, engineering means to enhance the desired function of MSC-exosomes has been rapidly gaining attention. In particular, biologically active molecule encapsulation and membrane modification can alter or enhance biological functions and targeting of MSC-exosomes. In this review, we summarize two possible strategies to improve the therapeutic activity of MSC-exosomes: preconditioning approaches and engineering exosomes. We also explore the underlying mechanisms of different strategies and discuss their advantages and limitations of the upcoming clinical applications.

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Section: Discussionmentioning

confidence: 99%

Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

Chen

Sun

Qian

et al. 2022

Stem Cells International

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“…More recently, a lysosome-associated membrane protein 2 isoform A (LAMP2A)-dependent mechanism was described as mediating the selective sorting of proteins into exosomes, particularly those containing KFERQ-like aminoacid sequences [ 61 ]. This mechanism was independent of the ESCRT machinery but relies on HSC70, CD63, Alix, Syntenin-1, Rab31, and ceramides.…”

Section: Exosomesmentioning

confidence: 99%

The Footprint of Exosomes in the Radiation-Induced Bystander Effects

et al. 2022

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Radiation therapy is widely used as the primary treatment option for several cancer types. However, radiation therapy is a nonspecific method and associated with significant challenges such as radioresistance and non-targeted effects. The radiation-induced non-targeted effects on nonirradiated cells nearby are known as bystander effects, while effects far from the ionising radiation-exposed cells are known as abscopal effects. These effects are presented as a consequence of intercellular communications. Therefore, a better understanding of the involved intercellular signals may bring promising new strategies for radiation risk assessment and potential targets for developing novel radiotherapy strategies. Recent studies indicate that radiation-derived extracellular vesicles, particularly exosomes, play a vital role in intercellular communications and may result in radioresistance and non-targeted effects. This review describes exosome biology, intercellular interactions, and response to different environmental stressors and diseases, and focuses on their role as functional mediators in inducing radiation-induced bystander effect (RIBE).

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“…However, reports show that depletion of HSC70 from cells decreases HSP40 presence in exosomes ( Kampinga and Craig, 2010 ). Additionally, a recent paper demonstrates that HSC70, and potentially other chaperones that directly interact with HSC70 (such as HSP40, HSP90, and others), are loaded into nascent exosomes by a mechanism dependent on the endo-lysosomal transmembrane receptor LAMP2A ( Ferreira et al, 2022 ). These observations indicate that there is a conserved molecular mechanism for the loading and transfer of molecular chaperones via exosomes, with the potential to boost proteostasis in a cell non-autonomous way.…”

Section: Cell Non-autonomous Coordination Of Proteostasismentioning

confidence: 99%

“…The mechanisms that regulate the loading of proteotoxic material into nascent exosomes are still a matter of debate. One way this could happen is through the trapping of misfolded proteins bound to the molecular chaperone HSC70, that is included in exosomes, either through the interaction with LAMP2A or by attaching to lipids, in the endosomal limiting membrane, where exosomes are formed ( Sahu et al, 2011 ; Ferreira et al, 2022 ).…”

Section: Cell Non-autonomous Coordination Of Proteostasismentioning

confidence: 99%

Cell Non-autonomous Proteostasis Regulation in Aging and Disease

2022

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Aging is a risk factor for a number of diseases, being the more notorious ones perhaps neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These and other age-related pathologies are often associated with accumulation of proteotoxic material inside cells, as well as with the accumulation of protein deposits extracellularly. It is widely accepted that this accumulation of toxic proteins trails a progressive decline in the mechanisms that regulate protein homeostasis, or proteostasis, during aging. However, despite significant efforts, the progress in terms of novel or improved therapies targeting accumulation of proteotoxic material has been rather limited. For example, clinical trials for new drugs aimed at treating Alzheimer’s disease, by preventing accumulation of toxic proteins, have notoriously failed. On the other hand, it is becoming increasingly apparent that regulation of proteostasis is not a cell autonomous process. In fact, cells rely on complex transcellular networks to maintain tissue and organ homeostasis involving endocrine and paracrine signaling pathways. In this review we will discuss the impact of cell non-autonomous proteostasis mechanisms and their impact in aging and disease. We will focus on how transcellular proteostasis networks can shed new light into stablished paradigms about the aging of organisms.

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LAMP2A regulates the loading of proteins into exosomes

Cited by 97 publications

References 59 publications

Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

The Footprint of Exosomes in the Radiation-Induced Bystander Effects

Cell Non-autonomous Proteostasis Regulation in Aging and Disease

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