Histone H3 threonine 11 phosphorylation by Sch9 and CK2 regulates chronological lifespan by controlling the nutritional stress response

Abstract

Upon nutritional stress, the metabolic status of cells is changed by nutrient signaling pathways to ensure survival. Altered metabolism by nutrient signaling pathways has been suggested to influence cellular lifespan. However, it remains unclear how chromatin regulation is involved in this process. Here, we found that histone H3 threonine 11 phosphorylation (H3pT11) functions as a marker for nutritional stress and aging. Sch9 and CK2 kinases cooperatively regulate H3pT11 under stress conditions. Importantly, H3pT11 defective mutants prolonged chronological lifespan (CLS) by altering nutritional stress responses. Thus, the phosphorylation of H3T11 by Sch9 and CK2 links a nutritional stress response to chromatin in the regulation of CLS.

Structural clusters of histone H3 and H4 residues regulate chronological lifespan inSaccharomyces cerevisiae

“…The Workman group showed that H3T11 was phosphorylated by both Sch9 and Cka1, and reported that Δsch9 and Δcka1 as well as H3T11A prolonged CL 20 . Although this seems opposite to our result where the phosphorylated mimic H3T11D showed CLE, we note that the Δsch9 mutant strain will facilitate activated expression of Msn2/4 stress response genes associated with CLE 40 , and it is not clear if the CLE observed was due to absence of H3T11 phosphorylation or induction of stress response genes.…”

“…Although this seems opposite to our result where the phosphorylated mimic H3T11D showed CLE, we note that the Δsch9 mutant strain will facilitate activated expression of Msn2/4 stress response genes associated with CLE 40 , and it is not clear if the CLE observed was due to absence of H3T11 phosphorylation or induction of stress response genes. A phosphorylated mimic H3T11D was not tested 20 .…”

“…The yeast silencing complex formed by Sir2, Sir3 and Sir4 was also shown to be important in lifespan regulation 18 , suggesting that heterochromatin is involved in this process 11 . Histone H3K4 methylation and H3T11 phosphorylation are the only histone modifications to date shown to affect chronological lifespan (CL) in yeast as opposed to representing a consequence of it 19,20 .…”

Nuclear Organization in Stress and Aging

“…Several dietary stresses, especially the best characterized caloric restriction (CR), but also high-fat or low-protein diet result in epigenetic modifications that are conserved across evolution. In S. cerevisiae , nutritional stress leads to increased phosphorylation of histone H3 threonine 11 (H3pT11) by Sch9 and CK2 kinases, a change that is implicated in transcriptional activation and accelerates aging [169]. Accordingly, H3T11A mutants have extended chronological lifespan and increased stress resistance [169].…”

“…In S. cerevisiae , nutritional stress leads to increased phosphorylation of histone H3 threonine 11 (H3pT11) by Sch9 and CK2 kinases, a change that is implicated in transcriptional activation and accelerates aging [169]. Accordingly, H3T11A mutants have extended chronological lifespan and increased stress resistance [169]. Also in yeast, a potential epistatic behavior was established between the loss of histone H4 N-terminal acetylation (caused by deletion of N-alpha-terminal acetyltransferase NAT4 ) and lifespan extension under CR conditions, since nat4 deletion mutants have extended lifespan under normal growth conditions but not under CR [170].…”