A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane
A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane
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DOI：
10.1101/2022.07.06.498903
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发表时间：
2022-07
期刊：
影响因子：
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通讯作者：
Shoken Lee;Holly Merta;J. W. C. Rodríguez;Shirin Bahmanyar
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作者：
Shoken Lee;Holly Merta;J. W. C. Rodríguez;Shirin Bahmanyar
脂类成分是细胞器同一性的决定因素；然而，内质网(ER)的内核膜(INM)结构域是否含有有助于其同一性的独特的脂类化学尚不清楚。在这里，我们证明了一个独特的INM脂质环境，富含二酰甘油，保护核-细胞骨架连接物SUN2免受泛素-蛋白酶体系统的局部降解。SUN2核质区的膜结合两亲性螺旋对脂质敏感，对其蛋白质稳定性是必不可少的。我们发现，蛋白磷酸酶CTDNEP1定位于INM，通过调节磷脂酸性磷酸酶Lipin 1来维持SUN2积累所必需的独特的INM脂环境。因此，INM脂环境通过直接的脂-蛋白相互作用来调节蛋白质的稳定性，这对与核膜相关的疾病的机制具有广泛的意义。
Lipid composition is a determinant of organelle identity; however, whether the inner nuclear membrane (INM) domain of the endoplasmic reticulum (ER) harbors a unique lipid chemistry that contributes to its identity is not known. Here, we demonstrate that a unique INM lipid environment enriched in diacylglycerol protects the nucleo-cytoskeletal linker Sun2 from local degradation by the ubiquitin-proteasome system. A membrane binding amphipathic helix in the nucleoplasmic domain of Sun2 senses INM lipids and is essential to its protein stability. We show that the protein phosphatase CTDNEP1 localizes to the INM to maintain a distinct INM lipid environment necessary for Sun2 accumulation through regulation of the phosphatidic acid phosphatase lipin 1. Thus, the INM lipid environment sculpts the INM proteome via direct lipid-protein interactions that regulate protein stability, which has broad implications for mechanisms of diseases associated with the nuclear envelope.