在出生后危機(jī)四伏的幾個(gè)小時(shí)里，在突然失去來(lái)自母親的食物供應(yīng)的情況下，新生哺乳動(dòng)物必須要能夠生存下來(lái)。在通常情況下，新生兒會(huì)啟動(dòng)一種代謝反應(yīng)以抵御饑餓直至喂給食物。這一生存反應(yīng)涉及一個(gè)稱作自噬的，調(diào)控內(nèi)部能源分解的過(guò)程。盡管自噬已充分得到證實(shí)，當(dāng)前對(duì)于體內(nèi)自噬的關(guān)鍵機(jī)制調(diào)控因子仍知之甚少。
來(lái)自Whitehead研究所的研究人員發(fā)現(xiàn)了一個(gè)營(yíng)養(yǎng)物感知酶家族Rag GTPases，證實(shí)其調(diào)控了mTORC1蛋白質(zhì)復(fù)合物的活性，mTORC1蛋白質(zhì)復(fù)合物抑制是新生兒自噬和生存的必要條件。這一研究發(fā)現(xiàn)發(fā)表在本周的《自然》（Nature）雜志上。
領(lǐng)導(dǎo)這一研究的是Whitehead研究所的成員David Sabatini，在早先的體外研究中Sabatini證實(shí)了：mTORC1可以通過(guò)與Rag GTPases的相互作用感知重要氨基酸的存在。
為了評(píng)估Rag GTPase-mTORC1的關(guān)系對(duì)于哺乳動(dòng)物的影響，實(shí)驗(yàn)室生成了一種能夠不斷表達(dá)活性GTPase RagA形式的遺傳工程小鼠，并將它們與野生型小鼠進(jìn)行了比較。在正常小鼠中，當(dāng)存在營(yíng)養(yǎng)物質(zhì)時(shí)RagA會(huì)被激活，從而開(kāi)啟mTORC1信號(hào)，調(diào)控響應(yīng)養(yǎng)分供應(yīng)的生物體生長(zhǎng)。如果小鼠被奪取營(yíng)養(yǎng)物質(zhì)，RagA關(guān)閉，會(huì)導(dǎo)致mTORC1失活，啟動(dòng)自噬幫助動(dòng)物度過(guò)困難時(shí)期直至下一次喂食。然而，在遺傳工程小鼠中，盡管缺乏有效養(yǎng)分，RagA持續(xù)的活性維持了mTORC1活化。mTORC1不會(huì)觸發(fā)自噬，動(dòng)物的代謝保持不變，造成其營(yíng)養(yǎng)危機(jī)和死亡。
abatini 說(shuō)：“發(fā)生在具有RagA酶的新生動(dòng)物身上的事件讓我們感到非常的吃驚。一個(gè)正常的新生動(dòng)物會(huì)在出生后一小時(shí)內(nèi)對(duì)這一情況做出響應(yīng)，然而攜帶RagA的新生動(dòng)物則不會(huì)，從而導(dǎo)致其死亡。由于它無(wú)法適應(yīng)，從根本上導(dǎo)致了一個(gè)巨大的能量和營(yíng)養(yǎng)危機(jī)。”
這些研究結(jié)果同樣讓論文的第一作者、Sabatini實(shí)驗(yàn)室的博士后研究人員Alejo Efeyan感到驚愕。
Efeyan 說(shuō)：“我們感到驚訝的是，沒(méi)有發(fā)現(xiàn)獨(dú)立于RagA對(duì)這一信號(hào)的抑制作用，這意味著沒(méi)有備用系統(tǒng)。除了已知的氨基酸傳感器功能，RagA還是一個(gè)更為廣泛的營(yíng)養(yǎng)傳感器。”
以往，Sabatini實(shí)驗(yàn)室在培養(yǎng)細(xì)胞中確定了RagA作為氨基酸傳感器的功能。當(dāng)Efeyan比較禁食新生RagA活性小鼠與攜帶正常RagA的禁食幼鼠的營(yíng)養(yǎng)水平時(shí)，發(fā)現(xiàn)RagA活性動(dòng)物不僅氨基酸減少，葡萄糖水平也處在危險(xiǎn)低水平。這些動(dòng)物不能夠“感知”兩者的減少，因此RagA活性幼鼠無(wú)法啟動(dòng)自噬，在出生數(shù)小時(shí)內(nèi)所有的幼鼠均死亡。
發(fā)現(xiàn)RagA的這一新功能表明關(guān)于營(yíng)養(yǎng)傳感的生物學(xué)仍然有許多未知，Sabatini和他的實(shí)驗(yàn)室將繼續(xù)對(duì)這一研究領(lǐng)域展開(kāi)調(diào)查。
doi:10.1038/nature11745
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PMID:
Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival
Alejo Efeyan,1, 2, 3, 4, 5 Roberto Zoncu,1, 2, 3, 4, 5 Steven Chang,1, 2, 3, 4, 5 Iwona Gumper,6 Harriet Snitkin,6 Rachel L. Wolfson,1, 2, 3, 4, 5 Oktay Kirak,1, 7 David D. Sabatini6 & David M. Sabatini1, 2, 3, 4, 5
The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors1. Cell-based studies showed that mTORC1 senses amino acids through the RagA–D family of GTPases2, 3 (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagAGTP) from its endogenous promoter. RagAGTP/GTP mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagAGTP/GTP neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-RagAGTP/GTP neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagAGTP/GTP mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagAGTP/GTP neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagAGTP/GTP neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagAGTP/GTP fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.
