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Nature:新生兒自噬機(jī)制的調(diào)控因子
發(fā)布時間:2015-3-5
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   在出生后危機(jī)四伏的幾個小時里,在突然失去來自母親的食物供應(yīng)的情況下,新生哺乳動物必須要能夠生存下來。在通常情況下,新生兒會啟動一種代謝反應(yīng)以抵御饑餓直至喂給食物。這一生存反應(yīng)涉及一個稱作自噬的,調(diào)控內(nèi)部能源分解的過程。盡管自噬已充分得到證實(shí),當(dāng)前對于體內(nèi)自噬的關(guān)鍵機(jī)制調(diào)控因子仍知之甚少。

   來自Whitehead研究所的研究人員發(fā)現(xiàn)了一個營養(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可以通過與Rag GTPases的相互作用感知重要氨基酸的存在。

   為了評估Rag GTPase-mTORC1的關(guān)系對于哺乳動物的影響,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)存在營養(yǎng)物質(zhì)時RagA會被激活,從而開啟mTORC1信號,調(diào)控響應(yīng)養(yǎng)分供應(yīng)的生物體生長。如果小鼠被奪取營養(yǎng)物質(zhì),RagA關(guān)閉,會導(dǎo)致mTORC1失活,啟動自噬幫助動物度過困難時期直至下一次喂食。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不會觸發(fā)自噬,動物的代謝保持不變,造成其營養(yǎng)危機(jī)和死亡。

    abatini 說:“發(fā)生在具有RagA酶的新生動物身上的事件讓我們感到非常的吃驚。一個正常的新生動物會在出生后一小時內(nèi)對這一情況做出響應(yīng),然而攜帶RagA的新生動物則不會,從而導(dǎo)致其死亡。由于它無法適應(yīng),從根本上導(dǎo)致了一個巨大的能量和營養(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:“我們感到驚訝的是,沒有發(fā)現(xiàn)獨(dú)立于RagA對這一信號的抑制作用,這意味著沒有備用系統(tǒng)。除了已知的氨基酸傳感器功能,RagA還是一個更為廣泛的營養(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的禁食幼鼠的營養(yǎng)水平時,發(fā)現(xiàn)RagA活性動物不僅氨基酸減少,葡萄糖水平也處在危險低水平。這些動物不能夠“感知”兩者的減少,因此RagA活性幼鼠無法啟動自噬,在出生數(shù)小時內(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)對這一研究領(lǐng)域展開調(diào)查。

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.

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