Abstract
The expression of the core autophagy kinase, Unc51-like kinase 1 (ULK1), is regulated transcriptionally and translationally by starvation-induced autophagy. However, how ULK1 is regulated during hypoxia is not well understood. Previously, we showed that ULK1 expression is induced by hypoxia stress. Here, we report a new ULK1-modulating microRNA, miR-93; its transcription is negatively correlated with the translation of ULK1 under hypoxic condition. miR-93 targets ULK1 and reduces its protein levels under hypoxia condition. miR-93 also inhibits hypoxia-induced autophagy by preventing LC3-I to LC3-II transition and P62 degradation; these processes are reversed by the overexpression of an endogenous miR-93 inhibitor. Re-expression of ULK1 without miR-93 response elements restores the hypoxia-induced autophagy which is inhibited by miR-93. Finally, we detected the effects of miR-93 on cell viability and apoptosis in noncancer cell lines and cancer cells. We found that miR-93 sustains the viability of MEFs (mouse embryonic fibroblasts) and inhibits its apoptosis under hypoxia. Thus, we conclude that miR-93 is involved in hypoxia-induced autophagy by regulating ULK1. Our results provide a new angle to understand the complicated regulation of the key autophagy kinase ULK1 during different stress conditions.
Highlights
Autophagy is a regulated and highly conserved process that can develop double-membraned autophagosomes to degrade large protein aggregates and damaged organelles upon fusing with lysosomes [1, 2]
We found that the expression of Unc51-like kinase 1 (ULK1) was upregulated but miR-93 level was declined under hypoxic condition
Immunofluorescence showed that the expression of ULK1 was declined and the P62 level was increased by miR-93 (Figure 2)
Summary
Autophagy is a regulated and highly conserved process that can develop double-membraned autophagosomes to degrade large protein aggregates and damaged organelles upon fusing with lysosomes [1, 2]. Autophagy can recycle intracellular energy resources when the cell is deficient in nutrients and remove cytotoxic proteins and damaged organelles under a lot of stress conditions including pathogen invasion, hypoxia, and mitochondrial depolarization [3,4,5]. MiRNAs are 17 ~ 22 nucleotide, noncoding and singlestranded RNA molecules playing a role in a variety of pathophysiologic processes including apoptosis, cell proliferation, and differentiation [20,21,22]. It targets multiple genes via blocking mRNA translation. We uncovered the regulating mechanism between miRNA-93, ULK1, and hypoxiainduced autophagy
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