Reversible HuR‐micro RNA binding controls extracellular export of miR‐122 and augments stress response

Abstract

micro RNA s (mi RNA s), the tiny but stable regulatory RNA s 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 mi RNA function, accelerates extracellular vesicle (EV)‐mediated export of mi RNA s in human cells. In stressed cells, HuR replaces mi RNP s from target messages and is both necessary and sufficient for the extracellular export of corresponding mi RNA s. HuR could reversibly bind mi RNA s to replace them from Ago2 and subsequently itself gets freed from bound mi RNA s upon ubiquitination. The ubiquitinated form of HuR is predominantly associated with multivesicular bodies ( MVB ) where HuR‐unbound mi RNA s also reside. These MVB ‐associated pool of mi RNA s 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. image HuR is shown to facilitate the extracellular export of mi RNA s by binding and unloading them at MVB s that through EVs release mi RNA s into the extracellular space. HuR‐mediated export of miR‐122 occurs in stressed human cells and promotes the stress response. Stress‐induced extracellular export of miR‐122 via EVs ensures stress response in liver cells. HuR is necessary and sufficient for EV‐mediated extracellular export of miRNAs. HuR binds miRNAs and unloads them from Ago2. HuR ubiquitination causes miRNA release on MVBs for EV‐mediated miRNA export to take place.