bims-smemid 2024-03-17 papers

J Biol Chem. 2024 Mar 08. pii: S0021-9258(24)01646-6. [Epub ahead of print] 107151

The Integrated Stress Response in metabolic adaptation.

The Integrated Stress Response (ISR) refers to signaling pathways initiated by stress-activated eIF2‹ kinases. Distinct eIF2‹ kinases respond to different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced eIF2‹ phosphorylation attenuates general mRNA translation and, at the same time, stimulates the preferential translation of specific downstream factors to orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding of ISR during metabolic stress adaptation. Here, I discuss those advances, reviewing among others the ISR activation mechanisms in response to amino acid deprivation and mitochondrial stress. In addition, I review how ISR regulates the amino acid metabolic pathways and how changes in the ISR impact the physiology and pathology of various disease models.

Keywords: ATF4; GCN1; GCN2; HRI; Integrated Stress Response; amino acid deprivation; cysteine; eIF2‹; glutathione; mitochondrial stress; serine biosynthesis

DOI: https://doi.org/10.1016/j.jbc.2024.107151

EMBO Rep. 2024 Mar 13.

PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Cheng Chen, Qianyu Liu, Wenjie Chen, Zhiyuan Gong, Bo Kang, Meihua Sui, Liming Huang, Ying-Jie Wang.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Keywords: Electron Transport Chain Complex; Human Naive Pluripotency; PRODH; Reactive Oxygen Species; mtOXPHOS

DOI: https://doi.org/10.1038/s44319-024-00110-z

Biochem Soc Trans. 2024 Mar 13. pii: BST20230506. [Epub ahead of print]

Beyond protein synthesis: non-translational functions of threonyl-tRNA synthetases.

Pallob Barai, Jie Chen.

Aminoacyl-tRNA synthetases (AARSs) play an indispensable role in the translation of mRNAs into proteins. It has become amply clear that AARSs also have non-canonical or non-translational, yet essential, functions in a myriad of cellular and developmental processes. In this mini-review we discuss the current understanding of the roles of threonyl-tRNA synthetase (TARS) beyond protein synthesis and the underlying mechanisms. The two proteins in eukaryotes - cytoplasmic TARS1 and mitochondrial TARS2 - exert their non-canonical functions in the regulation of gene expression, cell signaling, angiogenesis, inflammatory responses, and tumorigenesis. The TARS proteins utilize a range of biochemical mechanisms, including assembly of a translation initiation complex, unexpected protein-protein interactions that lead to activation or inhibition of intracellular signaling pathways, and cytokine-like signaling through cell surface receptors in inflammation and angiogenesis. It is likely that new functions and novel mechanisms will continue to emerge for these multi-talented proteins.

Keywords: aminoacyl-trna synthetase; non-canonical; non-translational; threonyl-tRNA synthetase

DOI: https://doi.org/10.1042/BST20230506