A decrease in amino acids can cause the production of proteins that can promote autophagy.Credit: Hybrid Medical Animation / Science Photo Library
Amino acids are critical to cellular health and central to regulating nutrient metabolism, gene expression and protein synthesis. A shortage of amino acids can trigger multiple survival mechanisms, including a ‘starvation-induced translational programme’. When this happens, the cell saves energy by shutting down protein synthesis and recycling cellular components (autophagy) to generate energy. But precisely how the cell balances these processes is unclear.
Maria Antonietta De Matteis and Diego di Bernardo at the Telethon Institute of Genetics and Medicine in Naples, together with researchers across Italy and the US, have identified a crucial regulatory protein involved in tuning protein synthesis and balancing autophagy under starvation conditions.
Amino acid starvation changes the activity of stress-related signalling pathways. These changes suppress a key protein involved in initiating protein synthesis called eIF2α. At the same time, a group of transcription factors are activated, boosting the expression of autophagy genes. However, genes induced by the starvation programme must be translated to proteins to promote autophagy and the biosynthesis of organelles that digest cellular components, such as lysosomes.
The researchers found that one of the transcription factors, called TFEB, targets and regulates the expression of the GADD34 gene and its associated protein in the earliest stages of starvation. GADD34 then re-activates eIF2α to allow for critical protein synthesis only, and also modulates autophagy. The team showed that GADD34 knockout cells displayed impaired autophagic processes.
“This finding adds a new piece to the puzzle of how the cell coordinates multiple signalling and regulatory pathways to maintain homeostasis in the face of environmental perturbations,” says di Bernardo. “It also offers GADD34 as a new target to modulate autophagy for therapeutic purposes in neurodegenerative disorders and cancer.”
