Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 6; pp. 2021 - 2026
• Main Authors: Yuan, Shiaulou, Li, Jade, Diener, Dennis R, Choma, Michael A, Rosenbaum, Joel L, Sun, Zhaoxia
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.02.2012; National Acad Sciences
• Series: From the Cover
• Subjects: Animals; Beat frequencies; Biological Sciences; Body Patterning; Cell growth; Cells; Cilia; Cilia - enzymology; Cilia - metabolism; Danio rerio; Embryos; Evolution, Molecular; Flagella; Gene expression regulation; Gene Knockdown Techniques; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Homeostasis; Humans; Modulated signal processing; Movement; Organ Size; Pathogenesis; Physiological regulation; Protein Biosynthesis; Protein synthesis; Rheology; Ribosomal Protein S6 Kinases - metabolism; sclerosis; Signal Transduction; Stem cells; Transcription Factors - metabolism; Tumor Suppressor Proteins - metabolism; Zebrafish; Zebrafish Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1112834109

The cilium serves as a cellular antenna by coordinating upstream environmental cues with numerous downstream signaling processes that are indispensable for the function of the cell. This role is supported by the revelation that defects of the cilium underlie an emerging class of human disorders, termed "ciliopathies." Although mounting interest in the cilium has demonstrated the essential role that the organelle plays in vertebrate development, homeostasis, and disease pathogenesis, the mechanisms regulating cilia morphology and function remain unclear. Here, we show that the target-of-rapamycin (TOR) growth pathway modulates cilia size and function during zebrafish development. Knockdown of tuberous sclerosis complex 1a (tsc1a), which encodes an upstream inhibitor of TOR complex 1 (Torc1), increases cilia length. In contrast, treatment of embryos with rapamycin, an inhibitor of Torc1, shortens cilia length. Overexpression of ribosomal protein S6 kinase 1 (S6k1), which encodes a downstream substrate of Torc1, lengthens cilia. Furthermore, we provide evidence that TOR-mediated cilia assembly is evolutionarily conserved and that protein synthesis is essential for this regulation. Finally, we demonstrate that TOR signaling and cilia length are pivotal for a variety of downstream ciliary functions, such as cilia motility, fluid flow generation, and the establishment of left-right body asymmetry. Our findings reveal a unique role for the TOR pathway in regulating cilia size through protein synthesis and suggest that appropriate and defined lengths are necessary for proper function of the cilium.