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CD47 interactions with exportin-1 limit the targeting of m⁷G-modified RNAs to extracellular vesicles.

ABSTRACT: CD47 is a marker of self and a signaling receptor for thrombospondin-1 that is also a component of extracellular vesicles (EVs) released by various cell types. Previous studies identified CD47-dependent functional effects of T cell EVs on target cells, mediated by delivery of their RNA contents, and enrichment of specific subsets of coding and noncoding RNAs in CD47⁺ EVs. Mass spectrometry was employed here to identify potential mechanisms by which CD47 regulates the trafficking of specific RNAs to EVs. Specific interactions of CD47 and its cytoplasmic adapter ubiquilin-1 with components of the exportin-1/Ran nuclear export complex were identified and confirmed by coimmunoprecipitation. Exportin-1 is known to regulate nuclear to cytoplasmic trafficking of 5'-7-methylguanosine (m⁷G)-modified microRNAs and mRNAs that interact with its cargo protein EIF4E. Interaction with CD47 was inhibited following alkylation of exportin-1 at Cys⁵²⁸ by its covalent inhibitor leptomycin B. Leptomycin B increased levels of m⁷G-modified RNAs, and their association with exportin-1 in EVs released from wild type but not CD47-deficient cells. In addition to perturbing nuclear to cytoplasmic transport, transcriptomic analyses of EVs released by wild type and CD47-deficient Jurkat T cells revealed a global CD47-dependent enrichment of m⁷G-modified microRNAs and mRNAs in EVs released by CD47-deficient cells. Correspondingly, decreasing CD47 expression in wild type cells or treatment with thrombospondin-1 enhanced levels of specific m⁷G-modified RNAs released in EVs, and re-expressing CD47 in CD47-deficient T cells decreased their levels. Therefore, CD47 signaling limits the trafficking of m⁷G-modified RNAs to EVs through physical interactions with the exportin-1/Ran transport complex.

SUBMITTER: Kaur S

PROVIDER: S-EPMC9411329 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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CD47 interactions with exportin-1 limit the targeting of m<sup>7</sup>G-modified RNAs to extracellular vesicles.

Kaur Sukhbir S Saldana Alejandra Cavazos AC Elkahloun Abdel G AG Petersen Jennifer D JD Arakelyan Anush A Singh Satya P SP Jenkins Lisa M LM Kuo Bethany B Reginauld Bianca B Jordan David G DG Tran Andy D AD Wu Weiwei W Zimmerberg Joshua J Margolis Leonid L Roberts David D DD

Journal of cell communication and signaling 20211129 3

CD47 is a marker of self and a signaling receptor for thrombospondin-1 that is also a component of extracellular vesicles (EVs) released by various cell types. Previous studies identified CD47-dependent functional effects of T cell EVs on target cells, mediated by delivery of their RNA contents, and enrichment of specific subsets of coding and noncoding RNAs in CD47<sup>+</sup> EVs. Mass spectrometry was employed here to identify potential mechanisms by which CD47 regulates the trafficking of sp ...[more]

PMID: 34841476

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Project description:We consider the adhesive interaction energy between a pair of vesicles in the strong adhesion limit, in which bending forces play a negligible role in determining vesicle shape compared to forces due to membrane stretching. Although force−distance or energy−distance relationships characterizing adhesive interactions between fluid bilayers are routinely measured using the surface forces apparatus, the atomic force microscope, and the biomembrane force probe, the interacting bilayers in these methods are supported on surfaces (e.g., mica sheet) and cannot be deformed. However, it is known that, in a suspension, vesicles composed of the same bilayer can deform by stretching or bending, and can also undergo changes in volume. Adhesively interacting vesicles can thus form flat regions in the contact zone, which will result in an enhanced interaction energy as compared to rigid vesicles. The focus of this paper is to examine the magnitude of the interaction energy between adhesively interacting, deformed vesicles relative to free, undeformed vesicles as a function of the intervesicle separation. The modification of the intervesicle interaction energy due to vesicle deformability can be calculated knowing the undeformed radius of the vesicles, R0, the bending modulus, k(b), the area expansion modulus, k(a), and the adhesive minimum, W(P)(0), and separation, D(P)(0), in the energy of interaction between two flat bilayers, which can be obtained from the force−distance measurements made using the above supported-bilayer methods. For vesicles with constant volumes, we show that adhesive potentials between nondeforming bilayers such as |W(P)(0)| 5 × 10(−4) mJ/m2, which are ordinarily considered weak in the colloidal physics literature, can result in significantly deep (>10×) energy minima due to increase in vesicle area and flattening in the contact region. If the osmotic expulsion of water across the vesicles driven by the tense, stretched membrane in the presence of an osmotically active solute is also taken into account, the vesicles can undergo additional deformation (flattening), which further enhances the adhesive interaction between them. Finally, equilibration of ions and solutes due to the concentration differences created by the osmotic exchange of water can lead to further enhancement of the adhesion energy. Our result of the progressively increasing adhesive interaction energy between vesicles in the above regimes could explain why suspensions of very weakly attractive vesicles may undergo flocculation and eventual instability due to separation of vesicles from the suspending fluid by gravity. The possibility of such an instability is an extremely important issue for concentrated vesicle-based products and applications such as fabric softeners, hair therapeutics and drug delivery.

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CD47 interactions with exportin-1 limit the targeting of m⁷G-modified RNAs to extracellular vesicles.

Publications

CD47 interactions with exportin-1 limit the targeting of m<sup>7</sup>G-modified RNAs to extracellular vesicles.

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CD47 interactions with exportin-1 limit the targeting of m7G-modified RNAs to extracellular vesicles.

Publications

CD47 interactions with exportin-1 limit the targeting of m&lt;sup&gt;7&lt;/sup&gt;G-modified RNAs to extracellular vesicles.

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OmicsDI is part of the ELIXIR infrastructure

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CD47 interactions with exportin-1 limit the targeting of m⁷G-modified RNAs to extracellular vesicles.

CD47 interactions with exportin-1 limit the targeting of m<sup>7</sup>G-modified RNAs to extracellular vesicles.