Roelants, FM; Chauhan, N; Muir, A; Davis, JC; Menon, AK; Levine, TP; Thorner, J; (2018) TOR Complex 2-regulated protein kinase Ypk1 controls sterol distribution by inhibiting StARkin domain-containing proteins located at plasma membrane-endoplasmic reticulum contact sites. Molecular Biology of the Cell , 29 (17) pp. 2037-2136. 10.1091/mbc.E18-04-0229.

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Abstract

In our proteome-wide screen (Muir et al. 2014 Elife), Ysp2 (also known as Lam2/Ltc4) was identified as a likely physiologically relevant target of TORC2-dependent protein kinase Ypk1 in the yeast Saccharomyces cerevisiae. Ysp2 was subsequently shown to be one of a new family of sterol-binding proteins located at plasma membrane (PM)-endoplasmic reticulum (ER) contact sites (Gatta et al. 2015 Elife). Here we document that Ysp2 and its paralog Lam4/Ltc3 are authentic Ypk1 substrates in vivo and show using genetic and biochemical criteria that Ypk1-mediated phosphorylation inhibits the ability of these proteins to promote retrograde transport of sterols from the PM to the ER. Furthermore, we provide evidence that a change in PM sterol homeostasis promotes cell survival under membrane-perturbing conditions known to activate TORC2-Ypk1 signaling. These observations define the underlying molecular basis of a new regulatory mechanism for cellular response to plasma membrane stress.

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