The phosphatidylinositol 4,5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation.
The Stt4 phosphatidylinositol 4-kinase has been shown to generate a pool of phosphatidylinositol 4-phosphate (PI4P) at the plasma membrane, critical for actin cytoskeleton organization and cell viability. To further understand the essential role of Stt4-mediated PI4P production, we performed a genetic screen using the stt4(ts) mutation to identify candidate regulators and effectors of PI4P. From this analysis, we identified several genes that have been previously implicated in lipid metabolism. In particular, we observed synthetic lethality when both sphingolipid and PI4P synthesis were modestly diminished. Consistent with these data, we show that the previously characterized phosphoinositide effectors, Slm1 and Slm2, which regulate actin organization, are also necessary for normal sphingolipid metabolism, at least in part through regulation of the calcium/calmodulin-dependent phosphatase calcineurin, which binds directly to both proteins. Additionally, we identify Isc1, an inositol phosphosphingolipid phospholipase C, as an additional target of Slm1 and Slm2 negative regulation. Together, our data suggest that Slm1 and Slm2 define a molecular link between phosphoinositide and sphingolipid signaling and thereby regulate actin cytoskeleton organization.
Tabuchi
Mitsuaki
M
Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0668, USA.
Audhya
Anjon
A
Parsons
Ainslie B
AB
Boone
Charles
C
Emr
Scott D
SD
D019870:1-Phosphatidylinositol 4-Kinase / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003598:Cytoskeletal Proteins; D006801:Humans; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000096:biosynthesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor); D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013107:Sphingolipids / Q000378:metabolism*; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
D000199:Actins; C493245:CRTC2 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C502930:Slm1 protein, S cerevisiae; C502931:Slm2 protein, S cerevisiae; D013107:Sphingolipids; D014157:Transcription Factors; D010770:Phosphotransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C112465:STT4 protein, S cerevisiae; C489795:MSS4 protein, S cerevisiae; D019703:Calcineurin; C419391:ISC1 protein, S cerevisiae; D010738:Type C Phospholipases