Keeping sphingolipid levels n ORM al

Abstract

Lipids are essential for life as the principal components of biomembranes. In addition, many lipids act as signaling molecules both in and outside the cell. For these structural and regulatory functions it is crucial that the abundance of different lipids is controlled in a coordinated fashion to maintain the right balance between them. Aberrations in this equilibrium could result in altered membrane fluidity, increased membrane permeability, or depletion of signaling precursors. Particularly in the plasma membrane, a delicate balance between major lipid classes, namely glycerophospholipids, sterols, and sphingolipids, is maintained. Whereas important paradigms of sterol regulation have emerged principally from the work of the Brown and Goldstein laboratory, little is yet known about the regulation of sphingolipid levels. Two reports from the laboratories of Jonathan Weissman and Amy Chang published in Nature and PNAS, respectively, have started to uncover a fascinating regulatory mechanism for sphingolipid synthesis by the evolutionarily conserved family of endoplasmic reticulum (ER)-resident Orm proteins (1, 2). Starting from the observation a few years ago that deletion of ORM genes reduces fitness of yeast grown on media containing agents that induce ER stress (3), Han et al. found the unfolded protein response (UPR) that monitors the ER and homeostatically regulates its functions activated in ORM mutants. A functional link to sphingolipid metabolism is provided by a comprehensive genetic analysis generated in the Weissman laboratory, showing that overexpression of Orm proteins has a genetic interaction profile similar to the one of the hypomorphic alleles of LCB1 and LCB2 , encoding subunits of serine–palmitoyl–transferase (SPT) that catalyze the committing step of sphingolipid synthesis in the ER. Conversely, deletion of the ORM genes resulted in a phenotypic signature opposite to that of lcb1 and lcb2 . Interestingly, both groups found that this relationship is reflected in a physical complex … 1E-mail: twalther{at}biochem.mpg.de.