Abstract
Cell apoptosis is one of the main pathological alterations during oxidative stress (OS) injury. Previously, we corroborated that nuclear factor-κB (NF-κB) transactivation confers apoptosis resistance against OS in mammalian cells, yet the underlying mechanisms remain enigmatic. Here we report that microRNA-19a (miR-19a) transcriptionally regulated by reactive oxygen species (ROS) production and NF-κB deactivation prevents OS-initiated cell apoptosis through cylindromatosis (CYLD) repression. CYLD contributes to OS-initiated cell apoptosis, for which NF-κB deactivation is essential. MiR-19a directly represses CYLD via targeting 3′ UTR of CYLD, thereby antagonizing OS-initiated apoptosis. CYLD repression by miR-19a restores the IKKβ phosphorylation, RelA disassociation from IκBα, IκBα polyubiquitination and degradation, RelA recruitment at VEGF gene promoter as well as VEGF secretion in the context of OS. Either pharmacological deactivation of NF-κB or genetic upregulation of CYLD compromises the apoptosis-resistant phenotypes of miR-19a. Furthermore, miR-19a is transcriptionally downregulated upon OS in two distinct processes that require ROS production and NF-κB deactivation. VEGF potentiates the ability of miR-19a to activate NF-κB and render apoptosis resistance. Our findings underscore a putative mechanism whereby CYLD repression-mediated and NF-κB transactivation-dependent miR-19a regulatory feedback loop prevents cell apoptosis in response to OS microenvironment.
Highlights
Oxidative stress (OS), a state that reflects the balance between the systemic manifestation of reactive oxygen species (ROS) and detoxification of reactive intermediates or the resulting tissue damage, has been found in a wide range of human diseases, including Alzheimer’s disease, pulmonary edema, stroke, myocardial infarction and acute kidney injury [1,2,3,4,5]
We investigated the distinct roles of miR-19a on cell apoptosis initiated by oxidative stress (OS) and identified the possible mechanism: restoration of CYLD repressionmediated nuclear factor-κB (NF-κB) transactivation
Consistent with our previous study [11], the inhibitory function of CYLD on NF-κB relies on its intact catalytic activity because expression of a catalytically inactive CYLDC601A mutant, in which cysteine601 is substituted by alanine, could not enhance the abundance of IκBα to the equivalent extent as wild-type CYLD did (Supplementary Figure 1A)
Summary
Oxidative stress (OS), a state that reflects the balance between the systemic manifestation of reactive oxygen species (ROS) and detoxification of reactive intermediates or the resulting tissue damage, has been found in a wide range of human diseases, including Alzheimer’s disease, pulmonary edema, stroke, myocardial infarction and acute kidney injury [1,2,3,4,5]. Following stimulation of tumour necrosis factor-α (TNF-α) or other cytokines, proteins bearing specific ubiquitin-binding domain denoted as UBD, form complex with the Lys 63-linked polyubiquitylation of receptor interacting protein 1 (RIP1) through recruiting TNF receptor-associated factors (TRAFs) [8]. The formation of this complex subsequently facilitates the TAK1-dependent phosphorylation of IKKβ, which in turn phosphorylates IκBα at Ser32/36, leading to IκBα disassociation from NFκB, assembly of Lys 48-linked polyubiquitylation of IκBα by SKP-CUL-F-box (SCF)-βTrCP E3 ligase, degradation of IκBα by 26S proteasome, nuclear translocation of NF-κB and transcription of NF-κB target genes [9]. Despite our recent work has elucidated that CYLD can serve as an apoptosis inducer under certain conditions [11], the biological functions of CYLD in OSinitiated cell apoptosis are hitherto poorly understood
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