Codon Usage and mRNA Stability are Translational Determinants of Cellular Response to Canonical Ferroptosis Inducers. (1st October 2022)

• Record Type: Journal Article
• Authors: Rashad, Sherif; Byrne, Shane R; Saigusa, Daisuke; Xiang, Jingdong; Zhou, Yuan; Zhang, Liyin; Begley, Thomas J; Tominaga, Teiji; Niizuma, Kuniyasu
• Is Part Of: Neuroscience. Volume 501(2022)
• Page Start: 103
• Page End: 130
• Publication Date: 2022-10-01
• Subjects: mRNA stability -- tRNA modifications -- Alkbh1 -- Ferroptosis -- Codon usage -- mRNA translation; AS Alternative splicing -- ActD Actinomycin D -- CHX Cycloheximide -- tRNA transfer RNA -- UHPLC-MS/MS Ultra high performance liquid chromatography-tandem mass spectromtery -- PCA Principal component analysis -- PLSR Partial least squares regression -- FIN Ferroptosis inducing agents -- Ferr-1 Ferrostatin-1 -- GSH Glutathione -- GSSG Oxidized Glutathione -- SAM S-adenosylmethionine -- SAH S-adenosyl homocysteine -- ORF Open read frame -- SE Skipped exons -- RI Retained introns -- AS Mutually exclusive exons -- A3SS Alternative 3-prime splice site -- A5SS Alternative 5-prime splice site -- SCU synonymous codon usage -- GCU Global codon usage -- m1A 1-methyladenosine; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2022.08.009
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Ferroptosis is a caspase independent cell death relevant to many diseases. Cellular response to Class I or II ferroptosis inducers is epitranscriptionally distinct. mRNA stability changes play important role in ferroptosis stress response. Codon usage and biases are distinct in cellular response to different ferroptosis inducers. Alkbh1 influences ferroptosis via translational repression and reprogramming. Abstract: Ferroptosis is a non-apoptotic cell death mechanism characterized by the generation of lipid peroxides. While many effectors in the ferroptosis pathway have been mapped, its epitranscriptional regulation is not yet fully understood. Ferroptosis can be induced via system xCT inhibition (Class I) or GPX4 inhibition (Class II). Previous works have revealed important differences in cellular response to different ferroptosis inducers. Importantly, blocking mRNA transcription or translation appears to protect cells against Class I ferroptosis inducing agents but not Class II. In this work, we examined the impact of blocking transcription (via Actinomycin D) or translation (via Cycloheximide) on Erastin (Class I) or RSL3 (Class II) induced ferroptosis. Blocking transcription or translation protected cells against Erastin but was detrimental against RSL3. Cycloheximide led to increased levels of GSH alone or when co-treated with Erastin via the activation of the reverse transsulfuration pathway. RNA sequencing analysis revealed early activation of a strong alternative splice program before observed changes in transcription. mRNA stability analysis revealed divergent mRNA stability changes in cellular response to Erastin or RSL3. Importantly, codon optimality biases were drastically different in either condition. Our data also implicated translation repression and rate as an important determinant of the cellular response to ferroptosis inducers. Given that mRNA stability and codon usage can be influenced via the tRNA epitranscriptome, we evaluated the role of a tRNA modifying enzyme in ferroptosis stress response. Alkbh1, a tRNA demethylase, led to translation repression and increased the resistance to Erastin but made cells more sensitive to RSL3.