{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T10:06:18Z","timestamp":1789553178388,"version":"build-2803163510"},"reference-count":120,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>In mammalian systems, translational responses to amino acid limitation are commonly framed as mechanistic target of rapamycin complex 1 (mTORC1) inhibition and activation of the general control nonderepressible 2 (GCN2)\u2013eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) arm of the integrated stress response. Suppressing initiation, however, does not immediately relieve aminoacylated transfer RNA shortages for ribosomes already engaged on messenger RNA. Transfer RNA charging and ribosome profiling reveal codon- and isoacceptor-specific elongation constraints. Across mouse NIH3T3 and several human cell systems, leucine deprivation often appears initiation-dominant but can produce UUA-biased pausing and frameshifting in selected cancer cells. Valine deprivation can prolong decoding at all four valine codons, whereas separate isoleucine-deprivation studies report AUU\/AUC-selective slowing, a cytoplasmic isoleucyl-tRNA synthetase 1 (IARS1)-linked isoleucine-to-valine signal in exogenous reporter peptides, and an isoleucine-to-methionine substitution signal of unresolved mechanism. Ribosome slowing can engage global, transcript-local, and quality-control feedback, but the inputs are stress- and system-dependent. We propose a two-layer kinetic framework separating (i) A-site competition among correct decoding, substitution, and abortive exit from (ii) collision formation set by ribosome influx and dwell time. It keeps protein quantity, sequence fidelity, retained function, and proteostasis cost separate, and defines a matched measurement roadmap from metabolite flux to protein function.<\/jats:p>","DOI":"10.3390\/biology15181629","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:06:37Z","timestamp":1789549597000},"page":"1629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems"],"prefix":"10.3390","volume":"15","author":[{"given":"Mutsuki","family":"Ojima","sequence":"first","affiliation":[{"name":"Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7194-3053","authenticated-orcid":false,"given":"Miwako","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Osaka, Japan"},{"name":"College of Sport and Health Science, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu 525-8577, Shiga, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-7937","authenticated-orcid":false,"given":"Dong-Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1126\/science.aab2674","article-title":"Sestrin2 is a leucine sensor for the mTORC1 pathway","volume":"351","author":"Wolfson","year":"2016","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1126\/science.aad2087","article-title":"Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway","volume":"351","author":"Saxton","year":"2016","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/nar\/gkae006","article-title":"Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions","volume":"52","author":"Misra","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11269","DOI":"10.1073\/pnas.0400541101","article-title":"Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells","volume":"101","author":"Vattem","year":"2004","journal-title":"Proc. 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