Sterol-regulated transmembrane protein TMEM86a couples LXR signaling to regulation of lysoplasmalogens in macrophages

Wouw, S.A.E. van; Berg, M. van den; Ouraoui, M. el; Meurs, A.; Kingma, J.; Ottenhoff, R.; Loix, M.; Hoeksema, M.A.; Prange, K.; Pasterkamp, G.; Hendriks, J.J.A.; Bogie, J.F.J.; Klinken, J.B. van; Vaz, F.M.; Jongejan, A.; Winther, M.P.J. de; Zelcer, N.

doi:doi:10.1016/j.jlr.2022.100325

Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X re-ceptor (LXR) transcription factors are important de-terminants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid meta-bolism. However, their role in governing the compo-sition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow-derived mac-rophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lyso-plasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum pro-tein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages...Show moreLysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X re-ceptor (LXR) transcription factors are important de-terminants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid meta-bolism. However, their role in governing the compo-sition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow-derived mac-rophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lyso-plasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum pro-tein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages and microglia and that it is highly expressed in TREM2 thorn / lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. We further show that both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, we demonstrate that overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Collectively, our findings implicate TMEM86a as a sterol-regulated lysoplasma-logenase in macrophages that contributes to sterol -dependent membrane remodeling.Show less

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Sterol-regulated transmembrane protein TMEM86a couples LXR signaling to regulation of lysoplasmalogens in macrophages