TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation

Wing-Hang Tong, Nunziata Maio, De-Liang Zhang, Erika M. Palmieri, Hayden Ollivierre, Manik C. Ghosh, Daniel W. McVicar and Tracey A. Rouault; Blood Advances 2018 2:1146-1156; doi: doi:10.1182/bloodadvances.2018015669

hese results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.
Interestingly, we showed that silencing of FXN and ISCU resulted in increased MEC17 levels and increased α-tubulin acetylation.
Extensive chromatin immunoprecipitation data collected at the FRDA locus, which contains an expanded trinucleotide repeat (GAA)n in the first intron of FXN, had shown that the levels of the heterochromatin mark H3K9me3 were enriched, whereas the levels of acetylated H3 and H4 were reduced. Our finding that decreased Fe-S cluster biogenesis resulted in decreased overall histone acetylation and increased H3K9me3 levels poses an interesting possibility of a negative feedback mechanism that potentiates a progressive loss of FXN expression in the postmitotic cells that are most severely affected in FRDA. Furthermore, our results showed that silencing of Fe-S cluster biogenesis factors reduced the levels of ELP3, a subunit of the Elongator complex that has roles in growth cone motility and axonal outgrowth. In addition, our studies revealed that silencing of FXN or ISCU induced the α-tubulin acetyltransferase MEC17, resulting in hyperacetylation of α-tubulin. Reversible acetylation of tubulin confers mechanical protection to microtubules51 and controls their interaction with cellular components52 and is critical for neuronal development and function, growth factor or apoptotic signaling, and cell cycle progression. Acetylation of K40 of α-tubulin is mainly controlled by the cytosolic acetyltransferase MEC17 and the cytosolic deacetylases HDAC6 and SIRT2. Notably, a mouse model of FRDA cardiomyopathy with ablation of FXN had increased mitochondrial protein acetylation that was attributed to a decrease in the mitochondrial NAD+/NADH ratio, which can lower the activity of the mitochondrial deacetylase SIRT3. Thus, our findings suggest that the roles of PDHc, ELP3, and MEC17 in the etiology of FRDA, GLRX5-related sideroblastic anemias, and other Fe-S cluster biogenesis disorders warrant further study.