Matthews Krista A, Kunte Amit S, Tambe-Ebot Edward, Rawson Robert B
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Genetics. 2009 Jan;181(1):119-28. doi: 10.1534/genetics.108.093450. Epub 2008 Nov 17.
Sterol regulatory element binding protein (SREBP) is a major transcriptional regulator of lipid metabolism. Nuclear Drosophila SREBP (dSREBP) is essential for larval development in Drosophila melanogaster but dispensable in adults. dSREBP(-) larvae die at second instar owing to loss of dSREBP-mediated transcription but survive to adulthood when fed fatty acids. Activation of SREBP requires two separate cleavages. Site-1 protease (S1P) cleaves in the luminal loop of the membrane-bound SREBP precursor, cutting it in two. The NH(2)- and COOH-terminal domains remain membrane bound owing to their single membrane-spanning helices. The NH(2)-terminal cleavage product is the substrate for site-2 protease (S2P), which cleaves within its membrane-spanning helix to release the transcription factor. In mice, loss of S1P is lethal but the consequences of loss of S2P in animals remain undefined. All known functions of SREBP require its cleavage by S2P. We isolated Drosophila mutants that eliminate all dS2P function (dS2P(-)). Unexpectedly, larvae lacking dS2P are viable. They are deficient in transcription of some dSREBP target genes but less so than larvae lacking dSREBP. Despite loss of dS2P, dSREBP is processed in mutant larvae. Therefore, larvae have an alternative cleavage mechanism for producing transcriptionally active dSREBP, and this permits survival of dS2P mutants.
固醇调节元件结合蛋白（SREBP）是脂质代谢的主要转录调节因子。果蝇核内的SREBP（dSREBP）对黑腹果蝇的幼虫发育至关重要，但对成虫而言并非必需。dSREBP缺失的幼虫由于dSREBP介导的转录缺失，在二龄幼虫期死亡，但喂食脂肪酸后可存活至成年。SREBP的激活需要两次单独的切割。位点1蛋白酶（S1P）在膜结合的SREBP前体的腔内环处切割，将其切成两部分。由于其单个跨膜螺旋，NH2-和COOH-末端结构域仍与膜结合。NH2-末端切割产物是位点2蛋白酶（S2P）的底物，S2P在其跨膜螺旋内切割以释放转录因子。在小鼠中，S1P缺失是致命的，但S2P缺失在动物中的后果尚不清楚。SREBP的所有已知功能都需要其被S2P切割。我们分离出了消除所有dS2P功能的果蝇突变体（dS2P缺失）。出乎意料的是，缺乏dS2P的幼虫是存活的。它们在一些dSREBP靶基因的转录方面存在缺陷，但比缺乏dSREBP的幼虫程度要轻。尽管dS2P缺失，但dSREBP在突变幼虫中仍被加工。因此，幼虫有一种产生转录活性dSREBP的替代切割机制，这使得dS2P突变体能够存活。
