Berraquero Modesto, Tallada Víctor A, Jimenez Juan
Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/Consejo Superior de Investigaciones Científicas, Carretera de Utrera Km1, 41013 Seville, Spain.
iScience. 2025 Feb 24;28(3):112096. doi: 10.1016/j.isci.2025.112096. eCollection 2025 Mar 21.
The EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC complex facilitates the biogenesis of the sterol transfer protein Lam6/Ltc1 at ER-plasma membrane and ER-mitochondria contact sites. Cells that lose EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, leading to surplus ergosterol, cold-sensitive growth, and mitochondrial dysfunctions. Remarkably, inhibition of ergosterol biosynthesis, but also fluidization of cell membranes to counteract their rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results suggest that EMC-assisted biogenesis of Lam6/Ltc1 may provide, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.
内质网中高度保守的跨膜伴侣EMC复合物在人类中与甾醇稳态及众多不同的细胞活动相关，这使得EMC发挥功能的机制成谜。利用裂殖酵母，我们证明EMC复合物在内质网-质膜和内质网-线粒体接触位点促进甾醇转运蛋白Lam6/Ltc1的生物发生。丧失EMC功能的细胞在线粒体基质中隔离未折叠的Lam6/Ltc1和其他蛋白质，导致麦角甾醇过剩、冷敏感生长及线粒体功能障碍。值得注意的是，抑制麦角甾醇生物合成以及使细胞膜流化以抵消其僵化作用，均可降低内质网未折叠蛋白反应，并挽救EMC缺陷细胞的生长和线粒体缺陷。这些结果表明，EMC辅助的Lam6/Ltc1生物发生可能通过甾醇稳态提供最佳膜流动性，以促进其他内质网-膜蛋白的生物发生。
