Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy
Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy
复制标题
色氨酸应激激活 EGFR-RAS 信号传导至 MTORC1 和 p38/MAPK，以维持翻译和 AHR 依赖性自噬
DOI：
10.1101/2023.01.16.523931
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Pfänder P
中科院分区：
文献类型：
--
作者：
Pfänder P
有限的供应和催化剂限制了肿瘤中的必需氨基酸色氨酸（Trp）。肿瘤如何在Trp应激下维持翻译仍不清楚。与其他氨基酸不同，Trp应激激活EGFR，从而增强巨胞饮作用和RAS信号传导至MTORC 1和p38/MAPK激酶，维持翻译。AHR形成Trp应激蛋白质组的一部分，并促进自噬以维持Trp水平和神经酰胺生物合成。因此，Trp限制性酶促翻译信号使其能够适应营养胁迫，将Trp置于氨基酸介导的胁迫反应中的独特位置。我们的研究结果挑战了目前认为Trp限制抑制MTORC 1和AHR的观点，并解释了这两种癌症驱动因素如何保持活性。具有增强的MTORC 1和AHR的胶质母细胞瘤患者亚组显示自噬特征，突出了MTORC 1-AHR串扰的临床相关性。高Trp或高神经酰胺的区域是相互排斥的，支持低Trp激活胶质母细胞瘤组织中的EGFR-MTORC 1-AHR轴。亮点在Trp应激下，EGFR-RAS信号激活巨胞饮，MTORC 1和p38。MTORC 1和p38驱动的翻译诱导AHR水平和活性。AHR增强神经酰胺和自噬，维持细胞内Trp。在胶质母细胞瘤中，神经酰胺定位于低Trp区域，高AHR与MTORC 1活性和自噬相关。
Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.HIGHLIGHTSUnder Trp stress,EGFR-RAS signaling activates macropinocytosis, MTORC1 and p38.MTORC1 and p38 driven translation induces AHR levels and activity.AHR enhances ceramides and autophagy, sustaining intracellular Trp.In glioblastoma, ceramides localize to low Trp areas, and high AHR associates with MTORC1 activity and autophagy.