Evolutionarily divergent mTOR remodels translatome for tissue regeneration

• Published in: Nature (London) 2023-08, Vol.620 (7972), p.163-171
• Main Authors: Zhulyn, Olena, Rosenblatt, Hannah D., Shokat, Leila, Dai, Shizhong, Kuzuoglu-Öztürk, Duygu, Zhang, Zijian, Ruggero, Davide, Shokat, Kevan M., Barna, Maria
• Format: Article
• Language: English
• Subjects: 14/1; 14/34; 14/63; 38/1; 38/91; 45/90; 631/136/334; 631/337/574; 631/532/489; 64/60; 82/1; Ambystoma mexicanum - physiology; Amino Acid Sequence; Amino acids; Amphibians; Amputation; Animals; Antioxidants - metabolism; Biological Evolution; Chemoreception; Extremities - physiology; Gene expression; Humanities and Social Sciences; Humans; Kinases; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; multidisciplinary; Nutrient transport; Nutrients - metabolism; Polyribosomes - genetics; Polyribosomes - metabolism; Protein Biosynthesis; Protein synthesis; Proteins; Regeneration - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Species Specificity; Sucrose; Tissue engineering; TOR protein; TOR Serine-Threonine Kinases - metabolism; Vertebrates; Wound Healing
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06365-1

An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot 1 . Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl ( Ambystoma mexicanum ). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential. Rapid activation of protein synthesis in the axolotl highlights the unanticipated impact of a translatome on orchestrating the early steps of wound healing and provides a missing link in our understanding of vertebrate regenerative potential.