整合应激反应 （integrated stress response ISR）是蛋白质稳态失调时诱发的信号中心调控网络，主要以控制蛋白质合成速率来实现。 2020年4月24日，美国贝勒医学院的 Mauro Costa-Mattioli 和UCSF大学的 Peter Walter 在 Science 上发表题为 The integrated stress response: From mechanism to disease 综述。 本综述总结了ISR调控机制以及ISR异常时如何导致复杂疾病发生，包括认知障碍、神经退行性疾病、肿瘤和糖尿病等。 最后作者指出开发出调控ISR的有效药 …

2024年11月19日 · The transcription factor Gcn4 is the key effector of the yeast ISR, while the highly conserved multiprotein bridging factor 1 (Mbf1; EDF1 in humans) was identified as a transcriptional coactivator of Gcn4.

2024年12月5日 · In yeast, multiprotein bridging factor 1 (Mbf1) has been proposed to function in the integrated stress response (ISR) as a transcriptional coactivator by mediating a direct interaction between general transcription machinery and the process's key effector, Gcn4. However, mounting evidence has demons …

Our biochemical and struc-tural analyses reveal that Mbf1 functions as a core ISR factor by interacting with collided ribosomes to mediate Gcn2 activation. We further show that Mbf1 serves no role as a transcriptional coactivator of Gcn4. Instead, Mbf1 is required for optimal stress-induced eukaryotic initiation factor 2a (eIF2 ) phosphor-

2024年6月6日 · In response to stress, eukaryotes activate the integrated stress response (ISR) via phosphorylation of eIF2α to promote the translation of pro-survival effector genes, such as GCN4 in yeast. Complementing the ISR is the target of rapamycin (TOR) pathway, which regulates eIF4E function.

2020年4月24日 · ISR-induced reduction in TC enables a portion of scanning ribosomes to initiate at the canonical AUG of the GCN4/ATF4 ORFs instead. Other uORF-containing mRNAs are also translated in response to ISR activation, including those encoding ATF5 ; CHOP (C/EBP-homologous protein) ; GADD34 ; and in neurons, OPHN1 . However, the …

If there is a basal level of eIF2α kinase that produces a small amount of unstable GCN4, regulatory inputs that stabilize this transcription factor could effectively stimulate ISR signaling. These studies highlight that ISR can be regulated through diverse mechanisms and do not necessarily require changes in eIF2α kinase activity.

2020年9月16日 · ISR signaling is initiated by stress-activated kinases that phosphorylate the α-subunit of the eIF2 complex, thereby inhibiting eIF2’s ability to deliver initiator methionyl-tRNA (Met-tRNA i ...

2024年6月6日 · Besides genes involving amino acid catabolism, Diamond et al. 1 observed upregulation of GCN4 in response to eIF4E depletion. As a transcription factor typically induced during ISR, GCN4-targeted genes promote amino acid biosynthesis. Surprisingly, translational upregulation of GCN4 upon eIF4E depletion is not accompanied by eIF2α phosphorylation.

2023年4月5日 · In addition to repressing cap-dependent translation initiation, Gcn2-mediated eIF2α phosphorylation in yeast simultaneously promotes the translation of the transcription factor Gcn4, inducing the ISR .