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

Autor: Andy D. Tran, Sukhbir Kaur, Alejandra Cavazos Saldana, Bianca Reginauld, Jennifer D. Petersen, David D. Roberts, Anush Arakelyan, Joshua Zimmerberg, Bethany Kuo, Leonid Margolis, Satya P. Singh, Lisa M. Miller Jenkins, Abdel G. Elkahloun, David G. Jordan, Weiwei Wu
Rok vydání: 2021
Předmět:
Zdroj: Journal of Cell Communication and Signaling. 16:397-419
ISSN: 1873-961X
1873-9601
DOI: 10.1007/s12079-021-00646-y
Popis: 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.
Databáze: OpenAIRE
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