{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe eukaryotic initiation factor 3 subunit f (eIF3f) emerges as a pivotal mediator in muscle homeostasis, where its activity is finely balanced between promoting skeletal muscle hypertrophy and serving as a target for degradation during muscle atrophy. Under catabolic conditions associated with cancer, AIDS, sepsis, and other systemic disorders, the E3 ubiquitin ligase MAFbx (Atrogin1) is dramatically upregulated, leading to the ubiquitination and proteasomal degradation of eIF3f. This loss of eIF3f diminishes key components of protein synthesis—downregulating the mTORC1 pathway and its downstream effectors such as S6K1—thereby contributing to the atrophic process. Conversely, maintaining or genetically activating eIF3f has been shown to promote muscle hypertrophy by enhancing muscle protein synthesis and structural protein expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDetailed mutational analyses have further pinpointed a conserved C-terminal domain within eIF3f as crucial for its polyubiquitination. Specifically, six lysine residues in this region are required for full MAFbx-directed ubiquitination and subsequent proteasomal degradation, underscoring a critical regulatory mechanism. Mutants of eIF3f that are insensitive to ubiquitination not only resist degradation but also demonstrate pronounced hypertrophic activity in both cell-based and in vivo models, effectively protecting against muscle loss during catabolic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementing these molecular insights, genetic studies in animal models have established that eIF3f is essential for proper development and muscle maintenance. Homozygous deletion of eIF3f results in early embryonic lethality, whereas heterozygous animals—although viable—exhibit reduced eIF3f levels, diminished protein synthesis, and compromised activation of the mTORC1 pathway. These deficits manifest as decreased muscle mass and an exacerbated atrophic response during conditions such as hindlimb immobilization, reinforcing the central role of eIF3f in regulating skeletal muscle mass."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julie Lagirand-Cantaloube, Nicolas Offner, Alfredo Csibi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2008.52"}], "href": "https://doi.org/10.1038/emboj.2008.52"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18354498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18354498"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alfredo Csibi, Karen Cornille, Marie-Pierre Leibovitch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0008994"}], "href": "https://doi.org/10.1371/journal.pone.0008994"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20126553"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20126553"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alfredo Csibi, Marie Pierre Leibovitch, Karen Cornille, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MAFbx/Atrogin-1 controls the activity of the initiation factor eIF3-f in skeletal muscle atrophy by targeting multiple C-terminal lysines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M807641200"}], "href": "https://doi.org/10.1074/jbc.M807641200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19073596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19073596"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Aurélie Docquier, Laura Pavlin, Audrey Raibon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/JP277841"}], "href": "https://doi.org/10.1113/JP277841"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31026345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31026345"}]}]}]}