Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis

5 years ago

Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis

Ibrahim Omar, John S. Parks, Abraham K. Gebre, Oren Rom, Michael Berger, Leonor Cohen-Daniel, Michael Aviram

Acquisition of a ‘quiescence programme’ by naive T cells is important to provide a stress-free environment and resistance to apoptosis while preserving their responsiveness to activating stimuli. Therefore, the survival and proper function of naive T cells depends on their ability to maintain quiescence. Recently we demonstrated that by preventing chronic unresolved endoplasmic reticulum (ER) stress, Schlafen2 (Slfn2) maintains a stress-free environment to conserve a pool of naive T cells ready to respond to a microbial invasion. These findings strongly suggest an intimate association between quiescence and stress signalling. However, the connection between ER stress conditions and loss of T-cell quiescence is unknown. Here we demonstrate that homeostasis of cholesterol and lipids, is disrupted in T cells and monocytes from Slfn2-mutant, elektra, mice with higher levels of lipid rafts and lipid droplets found in these cells. Moreover, elektra T cells had elevated levels of free cholesterol and cholesteryl ester due to increased de novo synthesis and higher levels of the enzyme HMG-CoA reductase. As cholesterol plays an important role in the transition of T cells from resting to active state, and ER regulates cholesterol and lipid synthesis, we suggest that regulation of cholesterol levels through the prevention of ER stress is an essential component of the mechanism by which Slfn2 regulates quiescence. Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis. Low-density lipoprotein uptake (a) and cholesterol efflux (b) of elektra T cells are comparable to that of wild-type T cells. Elevated cellular cholesterol (c) and cholesteryl ester (d) biosynthesis in elektra T cells, supported by elevated HMG-CoA reductase protein levels in these cells (e) with no elevation of HMG-CoA reductase mRNA and other SREBP2 target genes (f). Our results demonstrate that the loss of function mutation, elektra, in the quiescence factor Slfn2 leads to accumulation of cholesterol due to increased de novo synthesis in T cells. This study establishes a potential role for Slfn2 in maintaining quiescence through the inhibition of cholesterol's de novo synthesis.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/imm.12785