Regulation of sphingolipid biosynthesis by the morphogenesis checkpoint kinase Swe1.

Chauhan, Neha; Han, Gongshe; Niranjanakumari, Somashekarappa; Gable, Kenneth; Dunn, Teresa M.; Kohlwein, Sepp D.

doi:10.1074/jbc.a115.693200

Cited by 10 publications

(10 citation statements)

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“…This RxRxxS/Tp pattern corresponds to the reported consensus motif for yeast protein kinase 1 (Ypk1) and has so far not been observed for any other AGC kinase in yeast (Fig. B) . Ypk1 is critically involved in the response to changes in sphingolipid levels .…”

supporting

confidence: 75%

Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion

et al. 2016

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Sphingolipids are essential components of eukaryotic cells with important functions in membrane biology and cellular signaling. Their levels are tightly controlled and coordinated with the abundance of other membrane lipids. How sphingolipid homeostasis is achieved is not yet well understood. Studies performed primarily in yeast showed that the phosphorylation states of several enzymes and regulators of sphingolipid synthesis are important, although a global understanding for such regulation is lacking. Here, we used high-resolution mass-spectrometry-based proteomics and phosphoproteomics to analyze the cellular response to sphingolipid synthesis inhibition. Our dataset reveals that changes in protein phosphorylation, rather than protein abundance, dominate the response to blocking sphingolipid synthesis. We identified Ypk signaling as a pathway that is activated under these conditions, and we identified potential Ypk1 target proteins. Our data provide a rich resource for on-going mechanistic studies of key elements of the cellular response to the depletion of sphingolipid levels and the maintenance of sphingolipid homeostasis.

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supporting

confidence: 75%

Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion

et al. 2016

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“…What is now emerging in yeast is an intricate and complex system of regulating de novo sphingolipid biosynthesis through manipulation of the Orm proteins, with possible connections to ER to Golgi protein transport (Han et al 2010), phospholipid utilization and synthesis (Han et al 2010), nutrient uptake (Shimobayashi et al 2013), Ca 2+ /calcineurin signaling (Gururaj, Federman, and Chang 2013), cell cycle control (Chauhan et al 2017), and membrane remodeling/biogenesis (Liu et al 2012). This ability of Orm proteins to be responsive to multiple regulatory pathways underscores the important role that Orm1/2 play in maintaining tight control over cellular sphingolipid levels.…”

Section: Yeast Orm Proteins: Multiple Regulatory Pathways Emergingmentioning

confidence: 99%

Orm/ORMDL proteins: Gate guardians and master regulators

Davis

Muthukumar

Wattenberg

2018

Advances in Biological Regulation

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Sphingolipids comprise a diverse family of lipids that perform multiple functions in both structure of cellular membranes and intra- and inter-cellular signaling. The diversity of this family is generated by an array of enzymes that produce individual classes and molecular species of family members and enzymes which catabolize those lipids for recycling pathways. However, all of these lipids begin their lives with a single step, the condensation of an amino acid, almost always serine, and a fatty acyl-CoA, almost always the 16-carbon, saturated fatty acid, palmitate. The enzyme complex that accomplishes this condensation is serine palmitoyltransferase (SPT), a membrane-bound component of the endoplasmic reticulum. This places SPT in the unique position of regulating the production of the entire sphingolipid pool. Understanding how SPT activity is regulated is currently a central focus in the field of sphingolipid biology. In this review we examine the regulation of SPT activity by a set of small, membrane-bound proteins of the endoplasmic reticulum, the Orms (in yeast) and ORMDLs (in vertebrates). We discuss what is known about how these proteins act as homeostatic regulators by monitoring cellular levels of sphingolipid, but also how the Orms/ORMDLs regulate SPT in response to other stimuli. Finally, we discuss the intriguing connection between one of the mammalian ORMDL isoforms, ORMDL3, and the pervasive pulmonary disease, asthma, in humans.

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“…The phosphorylation of Orm proteins by Npr1 regulates complex sphingolipid synthesis . In addition, cell cycle checkpoint kinase Swe1 is also involved in the phosphorylation of Orm proteins and the regulation of SPT activity in a Ypk1‐independent manner . When cells are treated with myriocin, the phosphorylation of Orm proteins increases in response to the reduction in sphingolipid production, indicating that Orm proteins function as mediators of homeostasis of sphingolipid biosynthesis .…”

Section: Introductionmentioning

confidence: 99%

Yeast lacking the amphiphysin family protein Rvs167 is sensitive to disruptions in sphingolipid levels

Toume

Tani

2016

The FEBS Journal

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Rvs167 and Rvs161 in Saccharomyces cerevisiae are amphiphysin family proteins, which are involved in several important cellular events, such as invagination and scission of endocytic vesicles, and actin cytoskeleton organization. It has been reported that cellular dysfunctions caused by deletion of RVS167 or RVS161 are rescued by deletion of specific nonessential sphingolipid-metabolizing enzyme genes. Here, we found that yeast cells lacking RVS167 or RVS161 exhibit a decrease in sphingolipid levels. In rvs167Δ cells, the expression level of Orm2, a negative regulator of serine palmitoyltransferase (SPT) catalyzing the initial step of sphingolipid biosynthesis, was increased in a calcineurin-dependent manner, and the decrease in sphingolipid levels in rvs167Δ cells was reversed on deletion of ORM2. Moreover, repression of both ORM1 and ORM2 expression or overexpression of SPT caused a strong growth defect of rvs167Δ cells, indicating that enhancement of de novo sphingolipid biosynthesis is detrimental to rvs167Δ cells. In contrast, partial repression of LCB1-encoding SPT suppressed abnormal phenotypes caused by the deletion of RVS167, including supersensitivity to high temperature and salt stress, and impairment of endocytosis and actin cytoskeleton organization. In addition, the partial repression of SPT activity suppressed the temperature supersensitivity and abnormal vacuolar morphology caused by deletion of VPS1 encoding a dynamin-like GTPase, which is required for vesicle scission and is functionally closely related to Rvs167/Rvs161, whereas repression of both ORM1 and ORM2 expression in vps1Δ cells caused a growth defect. Thus, it was suggested that proper regulation of SPT activity is indispensable for amphiphysindeficient cells.

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Regulation of sphingolipid biosynthesis by the morphogenesis checkpoint kinase Swe1.

Cited by 10 publications

References 0 publications

Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion

Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion

Orm/ORMDL proteins: Gate guardians and master regulators

Yeast lacking the amphiphysin family protein Rvs167 is sensitive to disruptions in sphingolipid levels

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