The epitranscriptomic writer ALKBH8 drives tolerance and protects mouse lungs from the environmental pollutant naphthalene

Abstract

The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a transfer RNA (tRNA) methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation of selenoproteins. Using Alkbh8 deficient ( Alkbh8 def ) mice, we have investigated the importance of epitranscriptomic systems in the response to naphthalene, an abundant polycyclic aromatic hydrocarbon and environmental toxicant. We performed basal lung analysis and naphthalene exposure studies using wild type (WT), Alkbh8 de f and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for naphthalene bioactivation. Under basal conditions, lungs from Alkbh8 def mice have increased markers of oxidative stress and decreased thioredoxin reductase protein levels, and have reprogrammed gene expression to differentially regulate stress response transcripts. Alkbh8 def mice are more sensitive to naphthalene induced death than WT, showing higher susceptibility to lung damage at the cellular and molecular levels. Further, WT mice develop a tolerance to naphthalene after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8 def mice. We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against naphthalene-induced lung dysfunction and promotes naphthalene tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo .

The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

“…For example, mouse KO of the tRNA modification enzyme Alkbh8 caused mismodification of several distinct tRNA isoacceptors at the critical wobble uridine position, but gave no overt phenotype 29 , 30 . However, later studies showed defects in selenoprotein synthesis and stress tolerance in the Alkbh8 KO mice 31 , 32 , and it was recently reported that homozygous inactivating mutations in the human ALKBH8 gene causes intellectual disability and general developmental delay 33 . Likewise, more detailed studies, e.g.…”

The Effect of tRNA[Ser]Sec Isopentenylation on Selenoprotein Expression

“…It is interesting that UGA/Sec re-coding in Gpx1 is not (always) sensitive to full mcm 5 U modification [ 59 ]. So, we wonder whether one could look at the available data in another way: formation of mcm 5 Um 34 in tRNAs is not unique for tRNA [Ser]Sec , but may represent a general mechanism to cope with oxidative stress [ 60 ].…”

Deciphering Epitranscriptome: Modification of mRNA Bases Provides a New Perspective for Post-transcriptional Regulation of Gene Expression

“…Epitranscriptomic base modifications have become an interesting topic of research and review, particularly in the animal system ( Meyer et al, 2012 ; Carlile et al, 2014 ; Fu Y. et al, 2014 ; Dominissini et al, 2016 ; Peer et al, 2017 ; Angelova et al, 2018 ; Arribas-Hernandez et al, 2018 ; Khoddami et al, 2019 ; Leonardi et al, 2020 ). Now, the epitranscriptomic modifications in plants like Arabidopsis ( Luo et al, 2014 ; Wan et al, 2015 ; Shen et al, 2016 ; Zuber et al, 2016 ; Cui Q. et al, 2017 ; David et al, 2017 ; Duan et al, 2017 ), rice ( Li Y. et al, 2014 ), maize ( Luo et al, 2019 ; Miao et al, 2019 ), and tomato ( Zhou et al, 2019 ) are also being studied.…”