Nuclear export modulates the cytoplasmic Sir2 homologue Hst2.
Modulating transcription factors is crucial to executing sophisticated gene expression programs. The silent information regulator 2 (Sir2) family of NAD-dependent protein deacetylases influences transcription by targeting proteins such as histones, p53 and forkhead-box family transcription factors. Although apparently cytoplasmic, both mammalian SIRT2 and its yeast orthologue Hst2 have been implicated in transcriptional regulation. Here, we show that Hst2 moves between the nucleus and cytoplasm, but is largely cytoplasmic owing to efficient nuclear export. This nuclear exclusion is mediated by the exportin chromosomal region maintenance 1 (Crm1) and a putative leucine-rich nuclear export sequence in Hst2, which overlaps a unique autoregulatory helix. Disruption of Hst2 export shows that nuclear exclusion inhibits the activity of Hst2 as a transcriptional repressor. Our identification of putative nuclear export sequences in numerous vertebrate SIRT2 proteins shows that active nuclear export can be a conserved mechanism for regulating Sir2 homologues.
Wilson
Jeanne M
JM
Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, 0347, La Jolla, California 92093, USA.
Le
Viet Q
VQ
Zimmerman
Collin
C
Marmorstein
Ronen
R
Pillus
Lorraine
L
D021581:Active Transport, Cell Nucleus; D000483:Alleles; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006655:Histone Deacetylases / Q000378:metabolism*; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic
D049790:Nuclear Export Signals; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C423033:HST2 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases