首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover
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Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover

机译:UBXD8和p97 / VCP的空间调控可控制ATGL介导的脂滴更新

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UBXD8 is a membrane-embedded recruitment factor for the p97/ VCP segregase that has been previously linked to endoplasmic re-ticulum (ER)-associated degradation and to the control of triacyl-glycerol synthesis in the ER. UBXD8 also has been identified as a component of cytoplasmic lipid droplets (LDs), but neither the mechanisms that control its trafficking between the ER and LDs nor its functions in the latter organelle have been investigated previously. Here we report that association of UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 specifically restricts trafficking of UBXD8 to LDs, and that the steady-state partitioning of UBXD8 between the ER and LDs can be experimentally manipulated by controlling the relative expression of these two proteins. We exploit this interaction to show that UBXD8-mediated recruitment of p97/VCP to LDs increases LD size by inhibiting the activity of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triacylglycerol hydrolysis. Our findings show that UBXD8 binds directly to ATGL and promotes dissociation of its endogenous coactivator, CGI-58. These data indicate that UBXD8 and p97/ VCP play central integrative roles in cellular energy homeostasis.
机译:UBXD8是p97 / VCP segregase的膜嵌入募集因子,先前已与内质网(ER)相关的降解以及ER中三酰基甘油合成的控制相关。 UBXD8也已被确定为细胞质脂质滴(LDs)的组成部分,但以前尚未研究过控制其在ER和LDs之间运输的机制,也未研究其在后者细胞器中的功能。在这里,我们报道UBXD8与内质网驻留的菱形假蛋白酶UBAC2的结合特别限制了UBXD8向LDs的运输,并且可以通过控制这两种蛋白的相对表达来实验性地操纵UBXD8在ER和LDs之间的稳态分配。我们利用这种相互作用来显示UBXD8介导的p97 / VCP到LD的募集通过抑制三酰甘油水解中的限速酶脂肪甘油三酸酯脂肪酶(ATGL)的活性来增加LD的大小。我们的发现表明,UBXD8直接与ATGL结合并促进其内源性共激活因子CGI-58的解离。这些数据表明UBXD8和p97 / VCP在细胞能量稳态中起着核心的整合作用。

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