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.
Highlights
MiRNAs, the 22-nucleotide-long noncoding RNAs, form miRNP complexes with Argonaute (AGO) proteins and regulate majority of genes by imperfect base pairing to the 30UTR of target messages [1].The majority of biochemical pathways in humans are miRNA controlled, and human diseases including several forms of cancer are associated with abnormal expression of miRNAs [2,3,4].miRNPs repress target genes either by inhibiting the translation or by affecting the stability of the target mRNAs [5,6]
Extracellular vesicle (EV)-mediated export is reported to be a key mechanism for lowering cellular miRNA content in human cells [10]
Starvation did not show any significant effect on the levels of extracellular vesicle (EV) released as marker proteins CD63 or HRS showed similar levels in EVs derived from Fed and
Summary
MiRNAs, the 22-nucleotide-long noncoding RNAs, form miRNP complexes with Argonaute (AGO) proteins and regulate majority of genes by imperfect base pairing to the 30UTR of target messages [1].The majority of biochemical pathways in humans are miRNA controlled, and human diseases including several forms of cancer are associated with abnormal expression of miRNAs [2,3,4].miRNPs repress target genes either by inhibiting the translation or by affecting the stability of the target mRNAs [5,6]. Despite being an important regulator of gene expression in eukaryotes, factors controlling miRNA stability in mammalian cells have remained largely unidentified Examples of both positive and negative feedback mechanisms to regulate miRNA level and activity mostly remain limited to specific miRNAs and are largely operative at miRNA synthesis and maturation steps [11]. MiRNAs are contained within cells but can be found in various body fluids including peripheral blood plasma, saliva, serum, and milk [12] These extracellular miRNAs are protected from degradation either by packaging in microvesicles (MVs) such as apoptotic bodies, shedding vesicles, and exosomes or even as part of free Ago proteins–miRNA complexes [13,14,15]. Recent report suggests stability of miRNAs may be controlled by extracellular export where impaired exosomal export in growth-retarded mammalian cells increases cellular miRNA level [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
