Abstract #47

Slm1 and Slm2 are novel substrates of the calcineurin phosphatase required for heat stress-induced endocytosis of the yeast uracil permease. Geert Bultynck¹, Victoria L. Heath¹, Alia P. Majeed¹, Jean-Marc Galan², Rosine Haguenauer-Tsapis², Martha S. Cyert¹. 1) Dept Biological Sci, Stanford Univ, Stanford, CA; 2) Institut Jacques Monod-CNRS, Universitie Paris VII, 2 place Jussieu, 75005 Paris, France.
   The Ca2+/calmodulin-dependent phosphatase, calcineurin, promotes yeast survival during environmental stress, and is active during heat stress. Slm1 and Slm2, related, PH-domain containing proteins that are redundant for an essential function, were identified as calcineurin substrates. Slm1 and Slm2 are required for sphingolipid-dependent processes. Slm proteins promote yeast cell growth in the presence of myriocin, an inhibitor of sphingolipid biosynthesis, and regulation of Slm proteins by calcineurin is required for their full activity under these conditions. Sphingoid bases, including phytosphingosine, are intermediates in sphingolipid biosynthesis that increase transiently during heat stress and induce cellular responses to heat stress. In vivo, either exposing cells to elevated temperature or adding phytosphingosine to the growth media induces dephosphorylation of Slms by calcineurin. During heat stress, sphingolipids signal turnover of the uracil permease, Fur4. In cells lacking Slm protein activity, stress induced endocytosis of Fur4 is blocked, and Fur4 accumulates at the cell surface in an ubiquitinated form. Furthermore, cells expressing a version of Slm2 that cannot be dephosphorylated by calcineurin display an increased rate of Fur4 turnover during heat stress. Thus, calcineurin may modulate sphingolipid-dependent events through regulation of Slm1 and Slm2. These findings, in combination with previous work identifying Slm1 and Slm2 as targets of Mss4/PIP2 and TORC2 signaling, suggest that Slm proteins integrate information from a variety of signaling pathways to coordinate the cellular response to heat stress.

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