Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery

Segel, Michael J.; Lash, Blake; Song, Jingwei; Ladha, Alim; Liu, Catherine C.; Jin, Xin; Mekhedov, Sergei; Macrae, Rhiannon K.; Koonin, Eugene V.; Zhang, Feng

doi:10.1126/science.abg6155

Cited by 282 publications

(276 citation statements)

References 59 publications

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“…A recently developed novel system for viral protein-mediated delivery and fusion with target cells is represented by the paternally expressed gene 10 (PEG10) [132] This gene product of retroelements as one of the mammalian gag homologs contributes to virus-like capsid formation that may also interact with cellular plasma membranes. Thereby, PEG10 can enable the transport of RNAs such as mRNAs and miRs among others into target cells [132,133]. Accordingly, the PEG10 system can deliver cargo to cells alternative to physiological vehicles like microvesicles or exosomes [134,135].…”

Section: Viral Fusogensmentioning

confidence: 99%

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Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

Dittmar

Weiler

Luo

et al. 2021

Cancers

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Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review.

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Section: Viral Fusogensmentioning

confidence: 99%

“…Moreover, the studies of Segel et al have demonstrated that the untranslated regions of PEG10 can be reprogrammed by inserting functional mRNAs of certain genes. By developing this system of selective endogenous encapsidation for cellular delivery (SEND), specific RNAs can be addressed, e.g., for therapeutic purposes [132].…”

Section: Viral Fusogensmentioning

confidence: 99%

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

Dittmar

Weiler

Luo

et al. 2021

Cancers

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show abstract

“…Nevertheless, Peg10 also maintains the ability to bind and package its own mRNA. This finding allowed to create an artificial packaging system where heterologous RNAs fused with Peg10-3 UTR were efficiently packed by Peg10 [200,201]. Furthermore, using the viral RNA packaging system, it became possible to specifically incorporate sgRNA with the CRISPR-Cas9 nuclease into EVs for genome editing [202].…”

Section: Exploitation Of Viral Sorting Mechanisms For Rna Loading Into Evsmentioning

confidence: 99%

Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes

Zubarev

Vladimirtsev

Воронцова

et al. 2021

Cells

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The advancement of precision medicine critically depends on the robustness and specificity of the carriers used for the targeted delivery of effector molecules in the human body. Numerous nanocarriers have been explored in vivo, to ensure the precise delivery of molecular cargos via tissue-specific targeting, including the endocrine part of the pancreas, thyroid, and adrenal glands. However, even after reaching the target organ, the cargo-carrying vehicle needs to enter the cell and then escape lysosomal destruction. Most artificial nanocarriers suffer from intrinsic limitations that prevent them from completing the specific delivery of the cargo. In this respect, extracellular vesicles (EVs) seem to be the natural tool for payload delivery due to their versatility and low toxicity. However, EV-mediated delivery is not selective and is usually short-ranged. By inserting the viral membrane fusion proteins into exosomes, it is possible to increase the efficiency of membrane recognition and also ease the process of membrane fusion. This review describes the molecular details of the viral-assisted interaction between the target cell and EVs. We also discuss the question of the usability of viral fusion proteins in developing extracellular vesicle-based nanocarriers with a higher efficacy of payload delivery. Finally, this review specifically highlights the role of Gag and RNA binding proteins in RNA sorting into EVs.

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“…Nevertheless, Peg10 also maintains the ability to bind and package its own mRNA. This finding allowed to create an artificial packaging system where heterologous RNAs fused with Peg10-3'UTR were efficiently packed by Peg10 [199,200]. Furthermore, using the viral RNA packaging system it became possible to specifically incorporate sgRNA with the CRISPR-Cas9 nuclease into extracellular vesicles for genome editing [201].…”

Section: Exploitation Of Viral Sorting Mechanisms For Rna Loading Into Extracellular Vesiclesmentioning

confidence: 99%

Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes

Zubarev¹,

Vladimirtsev²,

Воронцова³

et al. 2021

Preprint

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The advancement of precision medicine critically depends on the robustness and specificity of the carriers used for the targeted delivery of effector molecules in the human body. Numerous nanocarriers have been explored in vivo, to ensure the precise delivery of molecular cargos via tissue-specific targeting, including the endocrine part of the pancreas, thyroid, and adrenal glands. However, even after reaching the target organ, the cargo-carrying vehicle needs to enter the cell and then escape from lysosomal destruction. Most of artificial nanocarriers suffer from intrinsic limitations that either prevent them from completing the specific delivery of the cargo. In this respect, extracellular vesicles (EVs) seem to be the natural tool for payload delivery due to their versatility and low toxicity. However, EV-mediated delivery is not selective and usually short-ranged. By inserting the viral membrane fusion proteins into exosomes, it is possible to increase the efficiency of membrane recognition and also ease the process of membrane fusion. This review describes the molecular details of the viral-assisted interaction between the target cell and extracellular vesicles. We also discuss the question of the usability of viral fusion proteins in developing extracellular vesicle-based nanocarriers with higher efficacy of payload delivery. Finally, this review specifically highlights the role of Gag and RNA binding proteins in RNA sorting into extracellular vesicles.

show abstract

Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery

Cited by 282 publications

References 59 publications

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression

Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes

Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes

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