title: Reversible HuR-microRNA binding controls extracellular export of miR-122 and augments stress response.
abstract: microRNAs (miRNAs), the tiny but stable regulatory RNAs in metazoan cells, can undergo selective turnover in presence of specific internal and external cues to control cellular response against the changing environment. We have observed reduction in cellular miR-122 content, due to their accelerated extracellular export in human hepatic cells starved for small metabolites including amino acids. In this context, a new role of human ELAV protein HuR has been identified. HuR, a negative regulator of miRNA function, accelerates extracellular vesicle (EV)-mediated export of miRNAs in human cells. In stressed cells, HuR replaces miRNPs from target messages and is both necessary and sufficient for the extracellular export of corresponding miRNAs. HuR could reversibly bind miRNAs to replace them from Ago2 and subsequently itself gets freed from bound miRNAs upon ubiquitination. The ubiquitinated form of HuR is predominantly associated with multivesicular bodies (MVB) where HuR-unbound miRNAs also reside. These MVB-associated pool of miRNAs get exported out via EVs thereby delimiting cellular miR-122 level during starvation. Therefore, by modulating extracellular export of miR-122, HuR could control stress response in starved human hepatic cells.
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Mukherjee
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Bartika
authors.initials: B
authors.lastname: Ghoshal
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Souvik
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Yogaditya
authors.initials: Y
authors.lastname: Chakrabarty
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Shivaprasad
authors.initials: S
authors.lastname: Shwetha
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Saumitra
authors.initials: S
authors.lastname: Das
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India sb@csiriicb.in.
authors.forename: Suvendra N
authors.identifier: 0000-0001-9697-3824
authors.initials: SN
authors.lastname: Bhattacharyya
mesh_terms: D020413:3' Untranslated Regions; D060565:Argonaute Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D034443:RNA Transport; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D000067780:ELAV-Like Protein 1; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D058570:TOR Serine-Threonine Kinases
keywords: Ago; HuR; extracellular vesicles; miRNA export; miRNAs; ubiquitination