title: Spatiotemporal Uncoupling of MicroRNA-Mediated Translational Repression and Target RNA Degradation Controls MicroRNP Recycling in Mammalian Cells.
abstract: MicroRNA (miRNA)-mediated repression controls expression of more than half of protein-coding genes in metazoan animals. Translation repression is associated with target mRNA degradation initiated by decapping and deadenylation of the repressed mRNAs. Earlier evidence suggests the endoplasmic reticulum (ER) as the site where microRNPs (miRNPs) interact with their targets before translation repression sets in, but the subcellular location of subsequent degradation of miRNA-repressed messages is largely unidentified. Here, we explore the subcellular distribution of essential components of degradation machineries of miRNA-targeted mRNAs. We have noted that interaction of target mRNAs with AGO2 protein on the ER precedes the relocalization of repressed messages to multivesicular bodies (MVBs). The repressed messages subsequently get deadenylated, lose their interaction with AGO2, and become decapped. Blocking maturation of endosomes to late endosome and MVBs by targeting the endosomal protein HRS uncouples miRNA-mediated translation repression from target RNA degradation. HRS is also targeted by the intracellular parasite Leishmania donovani, which curtails the HRS level in infected cells to prevent uncoupling of mRNA-AGO2 interaction, preventing degradation of translationally repressed messages, and thus stops recycling of miRNPs preengaged in repression.
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Mainak
authors.initials: M
authors.lastname: Bose
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Bahnisikha
authors.initials: B
authors.lastname: Barman
authors.affiliation: RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Avijit
authors.initials: A
authors.lastname: Goswami
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.initials: SN
authors.lastname: Bhattacharyya
mesh_terms: D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007891:Leishmania / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D008322:Mammals / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D057146:Multivesicular Bodies / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D000067996:RAW 264.7 Cells; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D035683:MicroRNAs; D010750:Phosphoproteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate
keywords: RNA binding proteins; RNA stability; mRNA; mRNA degradation; translational control