TY - JOUR
T1 - Fpk1/2 kinases regulate cellular sphingoid long-chain base abundance and alter cellular resistance to LCB elevation or depletion
AU - Yamane-Sando, Yukari
AU - Shimobayashi, Etsuko
AU - Shimobayashi, Mitsugu
AU - Kozutsumi, Yasunori
AU - Oka, Shogo
AU - Takematsu, Hiromu
PY - 2014/4
Y1 - 2014/4
N2 - Sphingolipids are a family of eukaryotic lipids biosynthesized from sphingoid long-chain bases (LCBs). Sphingolipids are an essential class of lipids, as their depletion results in cell death. However, acute LCB supplementation is also toxic; thus, proper cellular LCB levels should be maintained. To characterize the "sphingolipid-signaling intercross," we performed a kinome screening assay in which budding yeast protein kinase-knockout strains were screened for resistance to ISP-1, a potent inhibitor of LCB biosynthesis. Here, one pair of such DIR (deletion-mediated ISP-1 resistance) genes, FPK1 and FPK2, was further characterized. Cellular LCB levels increased in the fpk1/2{increment} strain, which was hypersensitive to phytosphingosine (PHS), a major LCB species of yeast cells. Concomitantly, this strain acquired resistance to ISP-1. Fpk1 and Fpk2 were involved in two downstream events; that is, ISP-1 uptake due to aminophospholipid flippase and LCB degradation due to LCB4 expression. RSK3, which belongs to the p90-S6K subfamily, was identified as a functional counterpart of Fpk1/2 in mammalian cells as the RSK3 gene functionally complemented the ISP-1-resistant phenotype of fpk1/2{increment} cells.
AB - Sphingolipids are a family of eukaryotic lipids biosynthesized from sphingoid long-chain bases (LCBs). Sphingolipids are an essential class of lipids, as their depletion results in cell death. However, acute LCB supplementation is also toxic; thus, proper cellular LCB levels should be maintained. To characterize the "sphingolipid-signaling intercross," we performed a kinome screening assay in which budding yeast protein kinase-knockout strains were screened for resistance to ISP-1, a potent inhibitor of LCB biosynthesis. Here, one pair of such DIR (deletion-mediated ISP-1 resistance) genes, FPK1 and FPK2, was further characterized. Cellular LCB levels increased in the fpk1/2{increment} strain, which was hypersensitive to phytosphingosine (PHS), a major LCB species of yeast cells. Concomitantly, this strain acquired resistance to ISP-1. Fpk1 and Fpk2 were involved in two downstream events; that is, ISP-1 uptake due to aminophospholipid flippase and LCB degradation due to LCB4 expression. RSK3, which belongs to the p90-S6K subfamily, was identified as a functional counterpart of Fpk1/2 in mammalian cells as the RSK3 gene functionally complemented the ISP-1-resistant phenotype of fpk1/2{increment} cells.
UR - http://www.scopus.com/inward/record.url?scp=84898001219&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898001219&partnerID=8YFLogxK
U2 - 10.1002/mbo3.160
DO - 10.1002/mbo3.160
M3 - Article
C2 - 24510621
AN - SCOPUS:84898001219
VL - 3
SP - 196
EP - 212
JO - MicrobiologyOpen
JF - MicrobiologyOpen
SN - 2045-8827
IS - 2
ER -