Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis
Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis
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DOI：
10.1073/pnas.2018578117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Radhakrishnan, Arun
中科院分区：
文献类型：
--
作者：
Kober, Daniel L.;Xu, Shimeng;Radhakrishnan, Arun
动物细胞中的脂质稳态由固醇调节元件结合蛋白（SREBP）维持，所述固醇调节元件结合蛋白是膜结合转录因子，其蛋白水解激活需要胆固醇敏感膜蛋白Scap。在内质网（ER）膜中，SREBP的羧基末端结构域（CTD）与Scap的CTD结合。当胆固醇水平较低时，Scap将SREBP从ER护送到高尔基体，在高尔基体中，两种蛋白酶的作用释放SREBP的氨基末端结构域，其行进到细胞核以上调脂肪生成基因的表达。SREBP的CTD仍然与Scap结合，但必须消除，以便Scap可以再循环以结合和运输额外的SREBP。在这里，我们提供了深入了解这是如何发生的进行详细的分子解剖的CTD的SREBP 2，在哺乳动物中表达的三个SREBP亚型之一。我们确定了一个降解信号，由7个非连续的氨基酸编码的外显子19介导的SREBP2的蛋白酶体降解Scap的情况下。当与Scap的CTD结合时，该信号被掩蔽并且SREBP2被稳定。与Scap的结合需要SREBP 2的外显子18中的精氨酸残基。SREBP2在高尔基体中裂解后，其CTD保持与Scap结合，并与Scap一起返回ER，在ER中通过蛋白酶体降解消除。Scap结合基序，但不是降解信号，在SREBP 1中是保守的。SREBP 1的稳定性由其CTD的不同区域中的降解信号决定。这些发现突出了SREBP的CTD在调节SREBP活性中的先前未知的作用。
Lipid homeostasis in animal cells is maintained by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose proteolytic activation requires the cholesterol sensing membrane protein Scap. In endoplasmic reticulum (ER) membranes, the carboxyl-terminal domain (CTD) of SREBPs binds to the CTD of Scap. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi, where the actions of two pro teases release the amino-terminal domains of SREBPs that travel to the nucleus to up-regulate expression of lipogenic genes. The CTD of SREBP remains bound to Scap but must be eliminated so that Scap can be recycled to bind and transport additional SREBPs. Here, we provide insights into how this occurs by performing a detailed molecular dissection of the CTD of SREBP2, one of three SREBP isoforms expressed in mammals. We identify a degradation signal comprised of seven noncontiguous amino acids encoded in exon 19 that mediates SREBP2's proteasomal degradation in the absence of Scap. When bound to the CTD of Scap, this signal is masked and SREBP2 is stabilized. Binding to Scap requires an arginine residue in exon 18 of SREBP2. After SREBP2 is cleaved in Golgi, its CTD remains bound to Scap and returns to the ER with Scap where it is eliminated by proteasomal degradation. The Scap-binding motif, but not the degradation signal, is conserved in SREBP1. SREBP1's stability is determined by a degradation signal in a different region of its CTD. These findings highlight a previously unknown role for the CTD of SREBPs in regulating SREBP activity.