Back to Search
Start Over
Sip2, an N-Myristoylated β Subunit of Snf1 Kinase, Regulates Aging in Saccharomyces cerevisiae by Affecting Cellular Histone Kinase Activity, Recombination at rDNA Loci, and Silencing
- Source :
- Journal of Biological Chemistry. 278:13390-13397
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- Saccharomyces cerevisiae has evolved a number of mechanisms for sensing glucose. In the present study we examine the mechanism by which one of these pathways, involving Snf1, regulates cellular aging. Snf1 is a heterotrimer composed of a catalytic alpha subunit (Snf1p) that phosphorylates target proteins at Ser/Thr residues, an activating gamma subunit (Snf4p), and a beta subunit (Sip1p, Sip2p, or Gal83). We previously showed that forced expression of Snf1p or loss of Sip2p, but not the other beta subunits, causes accelerated aging, while removal of Snf4p extends life span (Ashrafi, K., Lin, S. S., Manchester, J. K., and Gordon, J. I. (2000) Genes Dev. 14, 1872-1885). We now demonstrate that in wild type cells, there is an age-associated shift in Sip2p from the plasma membrane to the cytoplasm, a prominent redistribution of Snf4p from the plasma membrane to the nucleus, a modest increase in nuclear Snf1p, and a concomitant increase in cellular Snf1 histone H3 kinase activity. Covalent attachment of myristate to the N-terminal Gly of Sip2p is essential for normal cellular life span. When plasma membrane association of Sip2p is abolished by a mutation that blocks its N-myristoylation, Snf4p is shifted to the nucleus. Rapidly aging sip2 Delta cells have higher levels of histone H3 kinase activity than their generation-matched isogenic wild type counterparts. Increased Snf1 activity is associated with augmented recombination at rDNA loci, plus desilencing at sites affected by Snf1-catalyzed Ser(10) phosphorylation of histone H3 (the INO1 promoter plus targets of the transcription factor Adr1p). The rapid-aging phenotype of sip2 Delta cells is fully rescued by blocking recombination at rDNA loci with a fob1 Delta allele; rescue is not accompanied by amelioration of an age-associated shift toward gluconeogenesis and glucose storage. Together, these findings suggest that Sip2p acts as a negative regulator of nuclear Snf1 activity in young cells by sequestering its activating gamma subunit at the plasma membrane and that loss of Sip2p from the plasma membrane to the cytoplasm in aging cells facilities Snf4p entry into the nucleus so that Snf1 can modify chromatin structure.
- Subjects :
- Recombination, Genetic
Saccharomyces cerevisiae Proteins
Protein subunit
Wild type
Protamine Kinase
Saccharomyces cerevisiae
Cell Biology
Protein Serine-Threonine Kinases
Biology
Histone kinase activity
DNA, Ribosomal
Biochemistry
Molecular biology
Recombinant Proteins
Kinetics
Protein Subunits
Histone H3
Trans-Activators
Gene Silencing
Kinase activity
Molecular Biology
Cell aging
G alpha subunit
Gamma subunit
Subjects
Details
- ISSN :
- 00219258 and 18721885
- Volume :
- 278
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1553cdbe551dcb941adc71f22e264449
- Full Text :
- https://doi.org/10.1074/jbc.m212818200